-------
A series of papers have appeared in the past two years describing the
effects of ozone on subjects greater than 50 years of age (Bedi et al., 1988;
Bedi and Horvath, 1987; Drechsler-Parks et al., 1987, 1988; Reisenauer et al.,
1988) (see Table 1).
Bedi and Horvath (1987) described the decrease in pulmonary function
response in a single subject studied at age 32 and again at age 40. The major
importance of this study is that it demonstrated a decline in response of
considerable magnitude (AFEV-j^ of -25% decreased to -5% over 8 years) that was
observed longitudinally. This lends credence to the results of the cross-
sectional studies indicating a decreased response in older subjects.
Drechsler-Parks et al. (1987) compared a group of older (age 51-76)
subjects exposed to 0.45 ppm ozone with a group of young adults studied under
the same protocol (2 hr intermittent exercise at 25 L/min). The older subj-ects
had substantially smaller changes in function than the younger subjects, both
male and female. FVC changes in the older subjects averaged -5.3% and, in the
young adults -14.1%. Similar differences were observed for other functional
measurements. Similar data for ozone exposure are reported in a second paper
by Drechsler-Parks et al. (1988).
Bedi et al. (1988) reported the results of a study in which older subjects
were exposed to this same ozone concentration (0.45 ppm) on three separate
occasions. The responses were not reproducible from one exposure to the next.
The group average did not change appreciably between exposure series indicating
that even though the older subjects have more variable responses they are
less responsive to ozone, as a group, than younger subjects.
Reisenauer et al. (1988) also studied a group of older subjects, age
55-74 years. These ozone exposures were conducted at 0.2 and 0.3 ppm ozone
using a light intermittent exercise regime. There were no significant changes
in FEV.^ Q. For the 0.3 ppm exposures, however, the female subjects (n=10)
had a slight rise (13%) in total respiratory resistance (R-,-) that was
statistically significant.
The implication of these differences in responsiveness to ozone in older
subjects is unclear. Only standard spirometry tests have been used to evaluate
responses. It is not known if changes in airway resistance or airway
responsiveness to methacholine or histamine are similarly attenuated in older
subjects. The possibility of inflammatory responses has not been studied in
these older subjects.
November 21, 1988 25 DRAFT—DO NOT QUOTE OR CITE
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Four publications (Eschenbacher et al., 1988; Kreit et.-al., 1988; Koenig
et al., 1988; Koenig et al., 1987) on the effects of ozone on asthmatics have
appeared recently (see Table 1). Also of interest is a recent study of subjects
with allergic rhinitis (McDonnell et al., 1987).
Kreit et al. (1988) studied nine asthmatics exposed to 0.4 ppm 0, for
2 hr while performing intermittent exercise with a ventilation of about
53 L/min. All subjects had a history of physician diagnosed asthma and were
sensitive to methacholine. Medications were withheld for at least 12 hr prior
to exposure. Nine nonasthmatic subjects were also studied under the same
protocol. Both groups of subjects had significant decreases in FVC, FEV-,,
FEV,,/FVC, ^^25-75' and 1C after ozone exposure. The changes in FEV-,,
FEV-j/FVC, and FEFp5-75 were more ne9ative in tne asthmatics than in the normals
(e.g., A% FEV, was -13.4% in normals and -23.1% in asthmatics). SRaw was not
significantly increased in normals but was in asthmatics after ozone exposure.
A significant increase in SRaw also occurred after air exposure in the asth-
matics. The change in SRaw after ozone was more than twice that after exercise
in air (ASRaw-air = +3.82; ASRaw-ozone = +8.02 cmH20-£~1-s~1). Both groups
experienced a similar relative decrease in methacholine responsiveness after
ozone exposure. It is important to note that these subjects underwent metha-
choline challenge both 90 min before and 90 min after exposure.
It is not clear to what extent the pre- and post-exposure challenge may
have confounded the results, particularly since the nonasthmatlcs received a
substantially larger dose of methacholine than the asthmatics. Normal subjects
appeared to have a depressed FEFp,- yc prior to exposure (~12% decrease after
methacholine challenge). There were no differences in ozone-induced symptom
responses between normals and asthmatics.
A second report of this study (Eschenbacher et al., 1988) additionally
included a description of the effects of indomethacin pretreatment in ozone-
exposed normal subjects. The data for asthmatics were those reported by
Kreit et al. (1988). Indomethacin pretreatment in normals caused a marked
decrease in ozone-induced spirometry changes (AFEV-.-0, = -21.5%; AFEV^-03 +
indomethacin = -10.6%). However, there was also a surprising, but substantial,
placebo effect suggesting a possible behavioral component in ozone response.
Indomethacin, an inhibitor of cyclooxygenase pathways of arachidonic acid
metabolism, had no effect on the increase in airway responsiveness caused by
ozone. Indomethacin appears to primarily block the "restrictive" (i.e.,
November 21, 1988 26 DRAFT—DO NOT QUOTE OR CITE
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decreased FVC) effect of ozone and does not alter the bronchoconstrictive or
airway reactivity responses. Of additional interest was the observation that
"normal" subjects in the indomethacin study had an FEV-, decrease, after an
identical protocol, which was not unlike the response of the asthmatics, thus
raising the question of the normality of the subjects or the possible
confounding effect of a pre-exposure methacholine challenge.
The responses of adolescent asthmatics to 0.12 ppm and 0.18 ppm 0- were
O
tested by Koenig et al. (1987). The mouthpiece exposure sequence consisted of
30 min rest followed by 10 min exercise.(V£ = 33 L/min). In addition to the
10 asthmatics, 10 healthy adolescents were also studied. There was a
significant increase in total respiratory resistance (forced oscillation
method) in both normals and asthmatics exposed to 0.18 ppm 0~. There were no
significant changes in FEV-j^ in either subject group. At 0.12 ppm 03, there
were no significant differences that could be attributed to ozone in either
asthmatics or normals.
Koenig et al. (1988) have also studied adolescent asthmatics (n=10) and
healthy adolescents (n=10) exposed to either air, 0.12 ppm 0,, 0.3 ppm N00, or
«J C-
the combination of 03 plus NO,,. The mouthpiece exposures lasted 60 min and
included two 15 min exercise periods during which ventilation averaged about
35 L/min. Medications were discontinued at least 4 hr prior to exposure. In
the asthmatics, an 11% decrease in FEF^ was observed after 0.12 ppm ozone
exposure. One of the subjects had an exceptionally large decrease in FEF5Q%
of -60%, which occurred approximately 20 min after the end of exposure. This
same subject did not have a large change in FEF5Qo, when exposed to 03 plus
N0£, suggesting that the response of this individual to ozone may have been
anomalous. There were no other responses attributed to ozone in this study,
either in normal or asthmatic subjects. The authors tentatively suggested that
adolescent asthmatics may be slightly more responsive to these low levels of
ozone. However, replication of these observations will be required before this
suggestion can be substantiated.
McDonnell et al. (1987) studied 26 subjects with allergic rhinitis to
determine if the presence of allergies was a predisposing factor for ozone
sensitivity. These allergic subjects had airway responses to histamine that
were similar to a comparable group of non-allergic subjects. Exposure to
0.18 ppm 0^ for 2 hr with heavy intermittent exercise caused increased respon-
siveness to histamine and a decrease in several spirometric variables. The
November 21, 1988 27 DRAFT—DO NOT QUOTE OR CITE
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only apparent difference between the allergic subjects and previously exposed
non-allergic subjects was a significant increase in airway resistance in the
allergic subjects. It appears that both allergic and asthmatic subjects have a
greater rise in airway resistance after ozone exposure than do normal subjects.
The relative order of airway responsiveness to ozone is normal < allergic <
asthmatic.
Between September 1987 and October 1988, a series of reports have been
presented or published concerning a study of apparent seasonal variation in
ozone responsiveness in residents of Los Angeles (Avol et a!., 1988; Hackney
and Linn, 1988; Hackney et al., 1988; Linn et al., 1988) (see Table 1). The
definitive report of this study is the journal publication by Linn et al.
(1988). From a large number of subjects tested for ozone responsiveness,
12 responsive and 13 nonresponsive subjects were selected to participate in
further testing. Characteristics of the subjects are presented below:
Nonresponders
Responders
Gender
8M/5F
5M/7F
Age
5 >30
2 >30
Health Status
All Normal
4 Normal,
6 Atopic
2 Asthmatic
Mean AFEV-,
+1%
-12.'
In all tests, subjects were exposed to 0.18 ppm ozone during two hours of
_-i o
intermittent heavy exercise (ventilation = 35 1-min -m -BSA) at 35°C and
35% RH. These 25 subjects participated in two more pairs of exposure to ozone
and clean air. The initial tests were conducted in late spring (1986) and the
followup tests occurred in late summer/early fall (1986) and again in winter
(early 1987). A subsequent followup test with a smaller number of'subjects
(17 of the 25) occurred in spring (1987). The differences between responsive
and nonresponsive subjects, which were of course significant at the time of
the first test, were no longer significant at the first two followup studies in
late summer and winter. This suggested the possibility that ambient oxidant
exposure during the summer months produced an "adaptation" response which
persisted for several months. This suggestion was further strengthened when a
reduced number of subjects were exposed to ozone again, one year later. At
this time, the responsive subjects appeared to regain their sensitivity to
ozone exposure. The mean absolute changes in FEV-j^ for the four exposures in
November 21, 1988
28
DRAFT—DO NOT QUOTE! OR CITE
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the responsive subjects were -385, -17, +16, -347 ml respectively for the
spring, fall, winter, and spring tests respectively. Corresponding changes for
the nonresponders were +28, +90, +34, +81 ml. Because the experimental design
was not optimal, these results need to viewed with caution and, as the authors
state, "it is not clear that these results can be generalized." Nevertheless,
these findings clearly suggest that results of experimental ozone exposures of
residents of high oxidant areas must be viewed with caution if frequent ambient
exposure was a possibility during the period of experimental exposure.
Additional information presented by Hackney et al. (1988) indicated that
8 of the 12 responders were reactive to methacholine and had a history of
respiratory allergies. In addition, 10 of the 12 responders had a history of
some symptomatic complaints when exposed to "smog". The authors suggested
that allergy or atopy may be a risk factor for excess response to ozone although
other studies have indicated that increased airway reactivity is not predictive
of ozone responsiveness. They further speculated that nonresponders could be
at increased risk for chronic health effects of cumulative ambient ozone
exposure since they would be less likely to avoid such exposures because of
their lack of symptomatic complaints.
Controlled human exposure studies reviewed in the EPA criteria document
have suggested that some impairment of exercise performance may be associated
with 03 exposure. Subjective statements made by individuals engaged in these
controlled studies indicate that the perception of pain occurring with deep
breathing may be an important factor that limits performance of continuous
heavy exercise at 03 concentrations >0.18 ppm. Studies by Gong et al. (1986)
and by Schelegle and Adams (1986) substantiate these earlier findings while a
third study by Under et al. (1988) suggests that small decrements in maximal
exercise performance may occur at 03 concentrations <0.18 ppm (see Table 1).
Gong et al. (1986) found that maximal performance tested after exposure of
endurance athletes continuously exercising at heavy work loads (V£ = 89 L/min)
for 1 hr in a hot environment was impaired in 0.20 ppm 0,. This level of 0-
exposure also reduced pulmonary function and enhanced respiratory symptoms and
airway responsiveness to histamine. Maximal performance was not impaired after
exposure in 0.12 ppm 03, despite small but significant group mean decrements
(5.6 percent) in FEVr Similarly, Schelegle and Adams (1986) found that
exercise performance, as determined by completion of the exposure protocol, was
November 21, 1988 29 DRAFT—DO NOT QUOTE OR CITE
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impaired following exposure of endurance athletes who were continuously exer-
cising at heavy work loads (VV = 87 L/min) for 1 hr at 03 concentrations
>0.18 ppm but not at 0.12 ppm. Significant decrements in pulmonary function
and increased respiratory symptoms also occurred at >0.18 ppm 0~.
The effect of ozone inhalation on performance of maximum exercise tests
was also studied by a group of Swiss investigators (Linder et al., 1988). [A
translation of this paper is available]. Twenty-four subjects (12M, 12F) were
studied while performing maximal incremental exercise tests. The maximum
exposure duration was 28 minutes and minimum was 16 minutes. The tests were
performed in clean air, 0.07 ppm, and 0.13 ppm in an environmental chamber
(24±C; 50% rh). Small significant (t-test) increases (2%) in FE1^ Q were
observed after clean air exposure. Except for women exposed to 0.13 ppm
(-1.4%), no changes in FEV-, were observed with ozone exposure. Performance on
the maximum exercise test was decreased 11% in women and 7% in men at 0.13 ppm
and 5% and 4% respectively at 0.07 ppm (p <0.05; t-test). During the tests
conducted at 0.13 ppm, there was also a small decrease (2.5 to 5%) in anaerobic
threshold, defined as the workload at which the venous lactate concentration
exceeded 4 mM. It is not clear to what extent the results of the exercise
performance tests may reflect behavioral responses to the odor of ozone.
There are a number of questions that may be raised about the paper by
Linder et al. (1988). From the graphical presentation of the data on FEV-., it
appears that no significant changes would be detected by an appropriate sta-
tistical analysis (i.e., an analysis of variance appropriate for repeated
measures, rather than multiple t-tests). The authors did not indicate whether
appropriate precautions were taken to randomize or "blind" the exposures.
Furthermore, no information is provided about the selection criteria for
subjects. Because the effects were reported for very low exposure concentra-
tions and brief exposure durations (maximum 28 minutes), it is important to
determine if these observations can be verified since they appear to be out of
line with previous studies of exercise performance during ozone exposure.
The data currently available indicate that reduction in exercise perform-
ance may occur in many well-conditioned athletes after performing continuous
heavy exercise for 1 hr at 0- concentrations :>0.18 ppm. These athletes are
capable of sustaining very high exercise minute ventilations (i.e., >80 L/min)
for 1 hr. Any performance decrements occurring at 0, concentrations <0.18 ppm
are less certain and need to be verified. It must be noted, however, that
November 21, 1988 30 DRAFT—DO NOT QUOTE OR CITE
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other environmental conditions, such as increased ambient temperature and/or
relative humidity, may independently affect subjective symptoms and may
independently impair exercise performance. Therefore, it may be difficult to
differentiate work performance effects caused by 0- from physiological or
behavioral effects caused by other conditions in the environment.
Studies utilizing longer exposure durations, particularly at lower levels
of exercise, have not been previously reviewed in the EPA criteria document.
Among the newer data, two studies (Folinsbee et al., 1988; Horstman et al.,
1988a,b) address the effects of ozone exposures for durations >2 hr (see
Table 1). The first of these studies was designed to determine the effects of
prolonged exposure to the present level of the 1-hr NAAQS for 03 (0.12 ppm) on
10 young adult subjects that are representative of individuals who spend most
of the day outdoors exercising at moderate intensities (e.g., adults performing
heavy labor). Subjects were exposed to either 0.0 or 0.12 ppm ozone for a
total of 6.6 hr. During the exposure, the subjects exercised for six periods
of 50 min each; each exercise period was followed by 10 min of spirometry
testing and rest. An additional 35 min for lunch was interposed between the
third and fourth exercise period. The ventilation during the exercise averaged
about 41.5 L/min and heart rate ranged from 108 to 124 beats/min.
Prolonged exposure to 0.12 ppm 03 resulted in progressively larger changes
in respiratory function and symptoms with time. By the end of 6.6 hr of expo-
sure, group mean changes were as follows: FEV-, had decreased 13.0 percent,
FVC had decreased 8.3 percent, and FEF25-75% nad decreased 17.4 percent. On
forced inspiratory tests, FIVC and FIVQ 5 were decreased 12.6 and 20.7 percent
respectively. Respiratory symptoms of cough and pain on deep inspiration
increased with the increasing duration of 0~ exposure. There was also a marked
increase (about twofold) in airway responsiveness to methacholine following
Og exposure. No changes were observed with clean air exposure. The changes in
lung function reported at the end of exposure were similar in magnitude to
those previously observed in healthy subjects performing at heavy levels of
exercise (V£ >60 L/min) in much higher ozone concentrations (>0.2 ppm) for
shorter durations (i.e., <2 hr).
The need for additional concentration-response information led to a
subsequent study using the same ozone exposure protocol. Twenty subjects were
exposed for 6.6 hr to four ozone concentrations (0.0, 0.08, 0.10, and 0.12 ppm)
in random order. The results of these two studies were reported, in part, at
November 21, 1988 31 DRAFT—DO NOT QUOTE OR CITE
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the 1988 U.S.-Dutch symposium (Horstman et al., 1988a) and at the 1988 Annual
APCA Meeting (Horstman et al., 1988b). The ventilation in this series was
slightly lower than in the first study, averaging 38.9 L/min. The FEV1 Q
decreased by 7, 7, and 12.3% at 0.08, 0.10, and 0.12 ppm respectively. The
airway resistance response to methacholine was increased by factors of 1.56,
1.89, and 2.21 respectively. There was also a significant increase in the
symptom of pain upon deep breath, a typical symptom of acute ozone exposure. A
complete report of this study is in preparation.
The study by Folinsbee et al. (1988) is the first clinical study to demon-
strate increased airway reactivity to inhaled bronchoconstrictors in subjects
exposed to low 0, concentrations for prolonged periods of time. Other studies
reported in the recent literature have identified these effects in humans
exposed to 03 for shorter durations (see Table 1). The study by McDonnell
et al. (1987) described an increase in airway reactivity to histamine in
26 healthy subjects with allergic rhinitis who were exposed to 0.18 ppm 03 for
2 hr while undergoing heavy (V"E = 64 L/min) intermittent exercise. Seltzer
et al. (1986), in a study of 10 healthy individuals exposed for 2 hr to air and
to either 0.4 or 0.6 ppm 0- while undergoing moderate intermittent exercise,
O i
observed an increase in the number of neutrophils in bronchoalveolar lavage
fluid 3 hr after 0- exposure. Furthermore, they observed an increase in airway
reactivity to methacholine following 03 exposure and their data were suggestive
of an association between the degree of inflammation and the increase in airway
reactivity.
A new series of reports by Koren et al. (1988a,b,c,d) have described the
inflammatory and biochemical changes in the airways consequent to ozone exposure
(see Table 1). In these studies, subjects were exposed to 0.40 ppm for 2 hr
while performing intermittent exercise (15 min exercise, 15 min rest) at a
ventilation of 70 L-min""1-^ L-min"1^2 BSA); i.e., the same protocol as used
by McDonnell et al., 1983. The main purpose of these studies was to examine
cellular and biochemical responses in the airways of ozone exposed subjects.
To accomplish this, bronchoalveolar lavage (BAL) was performed about 18 hr
after the ozone exposure. Standard lung function tests were also performed
before and after exposure. A mean decrease in FEV^ of 960 ml after ozone
exposure was reported. An eightfold increase in polymorphonuclear leukocytes
(neutrophils) was observed after ozone exposure, confirming the observations of
Seltzer et al. (1986). A twofold increase in protein, albumin, and IgG were
November 21, 1988 32 DRAFT-DO NOT QUOTE OR CITE
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indicative of increased epithelial permeability as previously suggested by the
technetium DTPA clearance studies of Kehrl et al. (1987). In addition to
confirmation of these previous findings Koren et al. (1988d) provided evidence
of stimulation of fibrogenic processes including increases in fibronectin
(6.4x), tissue factor (2.1x), Factor VII (1.8x), and urokinase plasminogen
activator (3.6x). There was a twofold increase in the level of prostaglandin
E2 (PGE2) and a similar elevation of the complement component C3a. Levels of
the leukotrienes LTC^ and LIB. were not affected.
Further evidence supporting the hypothesis that cyclooxygenase products of
arachidonic acid metabolism (prostaglandins, thromboxane) may play a role in
ozone-induced spirometry changes comes from a study by Schelegle et al. (1987).
These investigators demonstrated a significant attenuation of decrements in FVC
and FEV-j^ Q when subjects were treated with the cyclooxygenase inhibitor,
indomethacin, prior to ozone exposure. Subjects were exposed to 0.35 ppm for
1 hr of continuous exercise (60 L/min); FEV-^ Q decreased 26.3% on the no-drug
day but only 10.6% after indomethacin pretreatment.
The above studies indicate that the inflammatory process caused by ozone
exposure is promptly initiated (Seltzer et al., 1986) and persists for at least
18 hr (Koren et al., 1988d). The time course of this inflammatory response and
the 03 exposures necessary to initiate it, however, have not yet been fully
elucidated. Furthermore, these studies demonstrate that cells and enzymes
capable of causing damage to pulmonary tissues were increased and the proteins
which play a role in the fibrotic and fibrinolytic processes were elevated as a
result of ozone exposure. At the recent U.S./Dutch Symposium report, Koren
et al. (1988b) reported that an inflammatory response, as indicated by
increased levels of PMN, was also observed in BAL fluid from subjects exposed
to 0.1 ppm 03 for 6.6 hr (some protocol as Folinsbee et al., 1988). A complete
report of these studies will be forthcoming.
Graham et al. (1988) showed an increase in neutrophils (PMN) in nasal
lavage fluid collected from subjects exposed to 0.50 ppm for four hours at
rest. There was a 3.5 fold increase in nasal PMN's immediately after exposure
and this increased further (6.5 fold) by the following day (i.e., 20 hr later).
This study suggests that a nasal inflammatory response may serve as a qualita-
tive indicator of an inflammatory response in the lung.
Kehrl et al. (1987) observed an increased rate at which inhaled technetium
labeled DTPA diffused from the airway and alveoli into the bloodstream in
November 21, 1988 33 DRAFT—DO NOT QUOTE OR CITE
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eight healthy subjects who endured heavy exercise for 2 hr in 0.4 ppm 03>
Kehrl et al. (1988) reported results from an additional 16 subjects studied in
the same manner. For the combined group of 24 subjects exposed for 2 hr to
0.40 ppm ozone, the average rate of clearance of technetium labelled DTPA was
1.08%/min. This clearance rate was some 60% faster than that observed after
air exposure. The average ozone-induced decrement in FVC in these subjects was
QQm
-10%. This study confirms that clearance of ^"Tc-DTPA is accelerated after
ozone exposure and, in conjunction with the Koren et al. (1988) observations,
strongly suggests that this accelerated clearance is due, in part, to an
increased epithelial permeability within the lung. These changes in permeabil-
ity are most likely associated with acute inflammation and could potentially
allow better access of inhaled antigens and other substances to the submucosa.
Studies of these endpoints at lower 03 levels have not been completed.
These observations by Koren, Kehrl, and co-workers have raised the
question of whether acute inflammation occurs following exposure to low levels
of ozone for prolonged periods of time (>2 hr). Studies are now in progress to
determine if these recently identified ozone effects are occurring at low 03
concentrations (i.e., <0.12 ppm). This research will improve our understanding
of the nature of inflammatory responses, including the biochemical and
molecular changes in the lung, that occur in Og-exposed subjects.
A recent series of papers by Gerrity and co-workers examining ozone uptake
in the respiratory tract have important implications for modelling the health
effects of ozone exposure in man and for extrapolating data from animals to
man (see Table 1).
Gerrity et al. (1988) studied a group of 18 healthy young males to deter-
mine the fractional uptake of ozone by the upper respiratory tract, excluding
the larynx (URT), and by the lower respiratory tract, including the larynx
(LRT). In order to measure ozone concentrations during the breathing cycle, a
chemiluminescent ozone analyzer was modified to increase its response time.
Gas was sampled at the level of the posterior larynx from a tube inserted
through the nose. Mean inspired and mean expired (alveolar) values of
pharyngeal ozone concentration were used to compute the fractional uptake of
ozone in the URT and LRT. The investigators studied the effects of changes in
ozone concentration (0.1, 0.2, 0.4 ppm), breathing frequency (12 and 24 BPM)
and mode of breathing (nasal, oral, oronasal). The differences between the
various treatment conditions were small; the average URT uptake was about 40%
November 21, 1988 34 DRAFT—DO NOT QUOTE OR CITE
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and average LRT uptake was about 91% (of the ozone that reached the larynx)
resulting in an average total respiratory tract uptake of approximately 95%.
(In other words, of the ozone entering the URT, about 40% was removed. Of the
remaining 60% that reached the trachea, 913» of that ozone was removed. Total
uptake is therefore (40% + (0.91 x 60%) = 95). Increased frequency of
breathing caused a decreased fractional removal of ozone in both URT and LRT,
presumably because of decreased residence time in the airway and increased flow
rate. The lowest fractional removal of ozone in the URT occurred during nasal
breathing. The differences between nasal and oral or oronasal breathing,
however, were very small. The lack of significant differences between nasal
and oral breathing on 03-induced changes in lung function and respiratory
symptoms was recently reported by Hynes et al. (1988), also suggesting that
the mode of inhalation may not affect ozone uptake as much as previously
expected.
In a second paper, Gerrity and McDonnell (1988) reported the influence of
the ozone-induced change in breathing pattern on the ozone uptake efficiency.
Subjects were exposed to 0.4 ppm ozone during continuous 60 minute exercise at
a ventilation of about 40 L/min. At the end of the exposure, there was a 25%
reduction in spontaneous tidal volume and a 45% increase in breathing frequency.
Associated lung function changes included a 13% reduction in FVC and an 18%
reduction in FEV-,. The change in breathing pattern was accompanied by a 9%
reduction in the LRT ozone uptake efficiency (fractional LRT uptake decreased
from 68% to 62%). Total ozone uptake (about 80%), was only reduced about
4% because there was a slight increase in ozone uptake in the URT. The reduc-
tion in LRT ozone uptake was correlated with the decrease in tidal volume,
suggesting that an increased depth of inspiration increases the dose delivered
to the LRT. The ozone uptake "efficiencies" reported in these two papers are
not strictly comparable because the methods used to make the calculations of
ozone uptake were different in each paper. The authors suggested that the
reduction in tidal volume may act as a protective mechanism for the lower
airways but, that the loss of this response with repeated exposures may permit
increased ozone delivery to the lower respiratory tract.
Gerrity (1987) described a model of nasopharyngeal uptake of ozone using
data from various animal species, including man. The conclusion reached in
this analysis was that nasopharyngeal ozone uptake decreases with increasing
flow but that there was also a considerable species variation in uptake (see
Section 3.1.3.3 and Table 6).
November 21, 1988 35 DRAFT—DO NOT QUOTE OR CITE
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The observations of Gerrity and co-workers have important implications
for interpretation of heavy exercise studies. Increased tidal volume increased
LRT ozone delivery but there may be a limit beyond which increases in tidal
volume will not cause increased LRT ozone delivery. Further modeling studies
will hopefully address whether such a limit exists in the physiological range
of human ventilation.
Available data on respiratory tract uptake efficiency in humans appears
to fit the predicted model, making it possible to develop dose-response infor-
mation from the wealth of controlled human studies that have already been
published. The current likelihood of making animal-to-man extrapolations based
on this information and on the comparison of respiratory tract uptake of 03
across different mammalian species is discussed in Section 3.1.3.3.
3.1.2 Epidemiological Studies
Newer studies of acute respiratory effects are available that show
associations between ozone and respiratory effects. The results of many of
the newer studies are directionally consistent with the findings of human
controlled studies. Results of newer epidemiological studies, however, as
with the older literature, continue to be mixed, some studies showing associa-
tions of ozone with respiratory effects and others showing no such associations
or stronger associations with other pollutants or environmental variables.
Where statistically significant associations between ozone and respiratory
endpoints and measures have been reported, some of the newer studies have
raised provocative questions that deserve and require further research and
analysis. The newer epidemiological studies known to be in print or in press
are summarized in Table 3. Only those studies are discussed that have data
potentially or directly relevant to respiratory effects occurring in free-
living populations as the result of iacute exposures to ozone.
Bates and Sizto (1987) have reanalyzed earlier data (Bates and Sizto,
1983; Bates, 1985) and extended their analyses to more recent data (now
covering 1974 and 1976-1982) for examining correlations between environmental
variables and total respiratory admissions (TRA), TRA minus asthma (TRA-A), and
nonrespiratory admissions (NRA), separately, for 79 acute-care hospitals in
southern Ontario, Canada. Pollutant concentration data for Og, NO,,, S02> COH
November 21, 1988 36 DRAFT—DO NOT QUOTE OR CITE
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(coefficient of haze), and SO. were collected at 16 sampling stations, and 0^
and SOp at a 17th, in the Windsor and Peterborough areas and the 280-mile
corridor in between. Correlations were examined for relationships among
environmental variables and between environmental variables and three
categories of hospital admissions for winter (Jan.-Feb.) and summer (Jul.-Aug.).
The authors concluded that an association exists in southern Ontario
between 03 and total respiratory hospital admissions (TRA) and TRA minus asthma
in summer, but they note that these results are not in agreement with those of
Richards et al. (1981), who found no associations between 0, and admissions to
children's hospitals or emergency room visits in Los Angeles, where-0- levels
are higher than those in southern Ontario. They concluded, as well, that
aerosol sulfate levels [SO,"] explain the highest percentage variance in TRA
from pollution in summer, but are not correlated with TRA in winter. Finally,
they concluded that 0- and SO/~ may be surrogates for one or more other species
that travel with them in summer but not in winter, such as [H ] in the fine-
particle range.
In this study, Bates and Sizto (1987) specifically tested the maximal 8-hr
03 average for correlation with TRA. The Pearson correlation coefficient was
not affected by substitution of the 8-hr value in place of the mean of the
hourly 03 maxima previously used. The correlation between the 1-hr and 8-hr
maxima across all monitoring stations was 0.986, but the correlation at one
station tested was 0.867.
Using the same methodology, Bates and Sizto (1988) examined aerometric
and hospital admissions data for June, July, and August 1983 and for June in
the years 1979 through 1985, since June 1983 was observed to have ozone levels
higher than those in any July or August previously examined. Analyses showed
no excess respiratory admissions in June 1983. Furthermore, in years for
which excess hospital admissions were observed in June (1982 and 1985),
increased admissions were in the categories of "acute bronchitis" and "asthma,"
but not in other respiratory categories, a finding inconsistent with ozone-
associated excess admissions reported earlier. The authors concluded that
these findings cast doubt "on the primacy of ozone as the cause" of increased
admissions, and that there are reasons against attributing excess admissions
either to ozone or sulfate.
Raizenne and coworkers have reported on several aspects of studies of
children in two summer camps in Ontario (Raizenne et al., 1987; 1988), one at
Lake Couchiching (LC) about 100 km north of Toronto, Ontario, and one at a Girl
November 21, 1988 42 DRAFT—DO NOT QUOTE OR CITE
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Guide (GG) camp on the north shore of Lake Erie. In the LC study (Raizenne
et al., 1987) the strongest association between lung function and environmental
variables was found in nonasthmatics, with FVC decrements correlated (p <0.01)
with 24-hr lag functions for average S04=, PM2 5, and T. The association of
PEF with unlagged 1-hr 03 was statistically significant and the average slope
of the regression line was -2.7 (ml/sec/ppb). Temperature (T) was signifi-
cantly associated with all lung indices in nonasthmatics but not in asthmatics.
The average slope of PEF for T in nonasthmatics was -21.7, a much stronger
association of PEF with T than with 03. Coefficients of variation (CV%) were
stable across the daily morning and evening tests of pulmonary function.
Though asthmatics had somewhat larger CV%, no statistical differences in CV%
for a.m. versus p.m. tests were seen in either group. Activity or exercise
levels were not estimated, nor was amount of indoor (as on rainy days) versus
outdoor activity estimated (i.e., actual exposure as well as proportion of
higher versus lower exercise levels).
Raizenne et al. (1988) have recently presented preliminary data from the
study of the effects of air pollution on girls aged 8 to 14 who attended one of
three consecutive 2-week sessions of the Girl Guide camp on Lake Erie (June 29
through August 9, 1986). The health status of each camper participating in the
study (112 of 145) was characterized by questionnaires completed by parents, by
bronchial challenge (methacholine, Men), and by skin-prick tests for atopy.
The influence of air pollution episodes on lung function was examined by
comparing lung function responses for each girl on episode days with mean
responses on "control" days (the latter defined as days with a 1-hr ozone
maximum of <90 ppb; S04= <15 ug/m3; H2S04= <10 ug/m3). Additionally, lung
function on the morning following an ozone episode versus the average function
on control days was examined.
Maximum decrements of 3.5% and 7% for fEV^ Q and PEF, respectively, were
reported to be associated with four distinct air pollution episodes in which
03, H , and S04~ were all elevated. Only FEV-j^ Q changes were statistically
significant, on 2 episode days (one each in camp sessions 1 and 2). For each
camp session, the mean values for FVC, FEV-j^ Q, and MMEF exhibited a U-shaped
pattern over time; larger first-day decrements were followed by a subsequent,
more gradual return to baseline. This pattern was not observed for PEF. The
largest FEV-j^ Q and PEF decrements were observed in Mch+ children the morning
after (July 26) the highest ozone level measured (July 25) during the study.
In Mch- children, however, the FEV-j^ Q change was positive and the PEF change
November 21, 1988 43 DRAFT—DO NOT QUOTE OR CITE
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was negative, both on July 25 and July 26. In camp session three, improvement
in both FEV, n and PEF were noted. The authors postulated the exposure of
J_* U
campers in session three to a regional episode prior to their arrival in camp,
with recovery occurring while at camp. No hypothesis was put forward to
explain the positive FEV., Q change in Mch- children on the day of the highest
peak ozone level and on the day following. The lack of an aggregate analysis
and the presence of largely unexplained temporal trends in pulmonary function
make interpretation of these study results difficult. This report of the
study does not provide strong evidence fqr the effects of ozone or of air
pollution episodes on pulmonary function.
On July 25, when the 1-hr ozone level was elevated (143 ppb), 12 subjects
performed pre- and post-exercise spirometry (exercise level and resulting
minute ventilation not estimated). For this subset of subjects, post-exercise
FVC and FEV-, Q were observed to increase on control day tests and to decrease
on the episode day (results on the episode day were compared with the mean PFT
results for all control days). The function changes did not attain statistical
significance, however (Raizenne et al., 1988).
During the study of girls attending the Lake Erie residential camp,
investigators (Raizenne and Spengler, 1988) examined the use of heart rate as a
surrogate for pulmonary ventilation during daily activities. A dosimetric
model was developed using heart-rate data from a standardized exercise test and
from portable heart-rate recording devices. Individual exposure estimates were
developed, based on time-activity data, and were related to changes in lung
function observed in the children. For both ozone and sulfuric acid, the
slopes of function (PEFR) versus pollutant did not differ from zero when the
data were adjusted for dosimetry. Adjusted data for FEV^ Q were not reported.
From a study they conducted in 1984 at a YMCA summer camp (Fairview Lake)
in northwestern NJ, Spektor et al. (1988a) have reported associations between
0, and variations in respiratory functions for 91 children attending camp for
O
at least 2 weeks. Average slopes for the regressions between Og concentrations
and functions were significantly negative (p <0.05) for FVC, FEV-j^ Q, MMEF, and
PEFR for all children and for boys and girls separately. Comparable data were
obtained for cohort subsets (2-week campers). When data were truncated at a
heat stress index (THI) of 78°F, the average slopes for girls were reduced by
half for the data sets restricted to THI <78°F, eliminating significant differ-
ences in FEV., Q changes between girls and boys. Little or no comparable effect
of a heat stress component was seen in boys. Activity levels were not
November 21, 1988 44 DRAFT—DO NOT QUOTE OR CITE
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estimated, so that the VE component of the responses was not estimated for
individual children or for cohort subsets.
As reported by the authors, multiple regression analyses indicated that
the 03 concentration in the hour preceding spirometry, the cumulative daily 0~
exposure during the hours between 9 a.m. and the function measurement, ambient
temperature, and humidity were the most explanatory environmental variables
for daily variations in function, with the 1-hr 03 concentration having the
strongest influence. The authors calculated predicted average functional
decrements from the average slopes of the base data set (Table 1, Spektor
et al., 1988a), assuming the exposure-response curve to be linear, of: FVC,
4.9%; FEV, 7.7%; PEFR, 17%; and MMEF, 11%; for QS at the current standard of
120 ppb. Of the 91 children studied, 33 (36%) had individually statistically
significant FEV-L Q responses, with an average coefficient in that subset of
-2.97 ml/ppb, or about a 16% decrement—again assuming linearity—at 120 ppb
03. The values for the 2-week subsets are generally consistent directionally
with 03 concentrations in the respective 2-week periods and the total period.
Likewise, slopes for data truncated at <60 ppb and <80 ppb 03 show general
directional consistency with the 03 concentration data except for FEF?I- ?
Several considerations should be noted. Ozone and temperature are highly
correlated in this study, with evidence of effects of heat stress on ozone-
associated decrements in function. If the respiratory effects depend
nonlinearly on interactions between temperature (or THI) and ozone, this may
confound interpretation of the effects of ozone. Data were truncated at
60 and 80 ppb and the conclusion was drawn that ozone-associated effects
occurred at <60 ppb. A formal test for threshold would seem to be in order.
The differing number of pulmonary function test days does not appear to have
been adequately accounted for in the pooled analysis. The results of this
apparently well-conducted study might be strengthened by additional analyses.
As reported, calculated decrements at the level of the current standard should
be interpreted cautiously.
Reanalyzing data from the Mendham, New Jersey, day camp study (Bock
et al., 1985), Lioy et al. (1985) hypothesized that PEFR decrements associated
with a 4-day ozone episode (concentrations >0.12 ppm) persisted on subsequent
days. Lioy and Dyba have recently (1988) proposed, however, that a more likely
explanation is that the PEFR decrements seen were the result of the total ozone
dose rather than a persistence from one day to the next.
November 21, 1988 45 DRAFT—DO NOT QUOTE OR CITE
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In a study by Kinney, the effects of air pollutants on lung function were
measured by spirometry in children (ages 10-12, 90 male and 64 female) in
Kingston and Harrisman, TN, with spirometry done at least six times, >1 week
apart, from February through April 1981 (Kinney, 1986; cited in Kinney et al.,
1988). Ozone and other pollutants were monitored at a single site in central
Harriman. Temperature and aeroallergens were not measured. Values for FVC,
FEV75v, MMEF, and V75% were regressed (ordinary least squares model) on the
1-hr maximum 0- concentrations and on the 24-hr-average FP and FP-sulfate
concentrations. Ozone concentrations ranged from 3 to 63 ppb during the study.
Concentrations of other pollutants (S02, N02, TSP, IP, RSP, and FP) were not
reported. Slopes of all four lung function-ozone regressions were signifi-
cantly negative. A positive mean slope of MMEF on fine particle concentrations
was reported. As noted in Kinney et al. (1988), outdoor-only monitoring and
lack of time-activity data compromise the specification of true exposures; and
the low ozone concentrations present during the study detract from plausibility.
Vedal et al. (1987) have reported data from an 8-month panel study of
symptoms and from concurrent but successive 9-week PEFR studies in asthmatic
and nonasthmatic school children living in the Chestnut Ridge area of western
Pennsylvania. Neither respiratory symptoms nor PEFR was strongly associated
with any of the environmental variables, which included peak 1-hr ozone, N02,
S02> and CoH, and daily temperature. Level of PEFR on the previous day was the
strongest predictor of daily PEFR. True exposures to ozone and other pollutants
were probably misspecified, since data were obtained from only one monitor for
the whole area, except for S02, for which an average of values from 17 monitors
was used; and individual exposures and activity levels were not estimated.
Further, levels of ozone during this school-year study were low, ranging from
0 to 65 ppb, with a mean of 16 ppb.
Results for the 1980-1981 school year have been recently reported by
Dockery et al. (1988) from an ongoing study of the effects of ambient air
pollution on respiratory health in children living in six cities in the United
States: Watertown, MA; Kingston-Harriman, TN; Steubenville, OH; Portage, WI; a
geographically defined portion of St. Louis, MO; and Topeka, KS. Previous
results showed that the reported prevalence of chronic cough, bronchitis, and
chest illness increased by about a factor of two across the range of TSP and
S02 concentrations measured in the six cities. Lung function was determined at
school by spirometry and a respiratory illness and symptom questionnaire was
November 21, 1988 46 DRAFT-DO NOT QUOTE OR CITE
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completed by each child's parents. Pollutants measured included TSP and
particles <15 urn and <2.5 ym (PM15 and PM£ 5), ozone, N02, and S02- The
pulmonary function parameters measured were FVC, FEV-j^ Q, FEV0 7g, and MMEF.
Five respiratory illness or symptom categories were considered: bronchitis,
cough, chest illness, wheeze, and asthma.
No association was found between air pollutant levels and the pulmonary
function measures, including FEVQ 75 and MMEF, which are more sensitive
measures than FEV-, „ and FVC of small airway impairment. As in previously
reported results from earlier years of this study, chronic cough, bronchitis,
and chest illness were positively associated with all three measures of
particulate pollution—TSP, PM15, and PM2 5—but only associations with PM-,5
were statistically significant. Sulfur dioxide, which showed correlation with
the particulate measures, was much more weakly associated than particles with
the respiratory symptoms. The association of N02 with respiratory symptoms was
also weak. According to the authors, the "negative associations of respiratory
symptoms with ozone probably do not represent a protective effect of ozone, but
rather indicate the negative correlation between ozone and other pollutants."
In this context, it is worth noting that a recent reanalysis by Schwartz
et al. (1988) of the Los Angeles study of student nurses (Hammer et al., 1974)
showed no association between ozone and respiratory symptoms other than cough;
and the association between ozone and cough was not seen until peak 1-hr ozone
concentrations were "well above the current ambient standard for ozone"
(»0.12 ppm). The reanalysis was done by logistic regression models and
time-series methods; whereas a hockey-stick function was used in the original
analysis.
Spektor et al. (1988b) conducted a study of the effects of ozone in
ambient air on pulmonary function in 30 healthy adult nonsmokers (20 males,
all Caucasian; 10 females, 2 non-Caucasian) exercising outdoors each work day
(between 11:30 a.m. and 6:30 p.m., June 27-August 2, 1985, except for July 4
and 5) in Sterling Forest research park in Tuxedo, New York. A respiratory
questionnaire was administered before exercise and spirometry was performed
before and after exercise. The outdoor exercise regimen was selected by the
subject. Following each exercise stint, the subject measured his own pulse
rate. Ventilation (V£) for each exercise period was estimated from the
subject-reported heart-rate data, calibrated from heart-rate data recorded from
indoor treadmill exercise at a pace similar to the outdoor exercise level.
November 21, 1988 47 DRAFT—DO NOT QUOTE OR CITE
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For each subject, on each exercise day, pre- and post-exercise function
measurements were taken, and changes in function were determined for FVC,
FEV-jL 0, (FEV-j^ Q/FVC), PEFR, and FEF25-75' Subject-specific exposures were
estimated from duration of exercise, mean 0, concentration during the exercise
period, minute ventilation, and the tidal 03 inhaled during exercise. Pollut-
ants and environmental variables measured were: ozone, SOg, NOX, ambient
aerosols (PM-,5 and PM? 5), aerosol acidity and other fine-particle ions,
temperature, humidity, and wind speed and direction. Pulmonary function
variables were regressed on mean 0~ concentration during exercise for each
subject, as well as against the 03 concentration during exercise on the
preceding day. Interactions of other environmental variables with ozone were
tested.
All pulmonary function indices showed significant (p >0.01) ozone-
associated decrements. No clear effects from other variables on the effects
of ozone v/ere seen. Mean decrements were reported as smaller in 10 subjects
with VV >100 L/min than those in 10 subjects with V£ of 60 to 100 L/min or
those in 10 subjects with Vr <60 L/min. The decrements were reported to be
about twice as large as those seen in 1- to 2-hr chamber studies in which V£
levels were comparable. No association was found between pre-exercise lung
function and mean ozone concentration during exercise on the preceding day (no
persistence). No symptomatic responses were reported. Analysis of lung
function changes for ventilations of 50 to 80 L/min was reported by the authors
to indicate that the influence of V£ on lung function decrements peaks at about
80 L/min.
This study appears to offer qualitative substantiation of the effects of
ozone on respiratory function in populations engaging in continuous exercise
outdoors for short periods of time (15 to ca. 60 minutes; average duration of
ca. 30 minutes). In addition, it is useful for the hypotheses it generates.
As with many apparently well-designed studies, however, this study raises at
least as many questions as it answers. When conditions of field or epidemio-
logic studies begin to approximate those of controlled studies, and when data
are quantitatively compared by the investigators to those obtained in controlled
studies, methodologic considerations become all the more important. Thus,
several points regarding this study are worth mentioning.
Methodologically, the use of heart-rate data in the absence of actual
heart-rate monitors raises questions about whether (a) the pulse was taken soon
November 21, 1988 48 DRAFT—DO NOT QUOTE OR CITE
-------
enough after exercise to permit valid calculation of VV levels: (b) whether
the treadmill-exercise heart-rate data were obtained through steady-state or
through incremental workloads; but, perhaps more important, (c) whether the
VE levels, especially the higher levels apparently attained in some subjects,
were constant throughout the exercise period or whether they resulted from
end-of-run aerobic sprints, resulting in a post-exercise heart rate higher than
the prevailing rate during most of the exercise period. The latter would lead
to an overestimation of VE levels and of inhaled dose during exercise.
With regard to the statistical methods used, the estimation of effects in
the most sensitive subgroups is questionable. Individual slopes are highly
variable because of biological variation in pulmonary function changes, such
that individuals having the largest slopes are not necessarily the most sensi-
tive individuals. Furthermore, the observed slopes are more variable than the
true slopes because of sampling variability, resulting in a bias away from zero
of the average coefficient in the subgroup with large observed slopes.
Additional information would be helpful for determining the adequacy of
the exposure characterization in this study. For example, it is not clear
whether ozone concentrations were the same in the respective microenvironments
(macadam roads versus trails); or whether one group of exercisers (runners
versus walkers, for example) consistently chose one microenvironment over
another. In addition, aeroallergens were not measured, but would have been a
potentially useful exposure measure given the nature of the study site.
Kinney et al. (1988) recently published a critical evaluation of five
epidemiological studies of the effects on lung function of acute exposures
to ozone. In that review, they compared the coefficients of ozone-associated
lung function declines reported in those studies with data derived from a
synthesis by Hazucha of results of controlled studies. Hazucha modeled the
effects of VE in potentiating the effects of ozone on pulmonary function, using
pooled data from 2-hr chamber studies of healthy young adults exercising
intermittently. Kinney et al. (1988) re-expressed the data of Hazucha in units
consistent with the epidemiologic study results (assuming a linear relationship
between lung function decline and concentrations up to 100 ppb and using base-
line functions obtained in Kinney, 1986).
The resulting coefficients were reported as being larger than those from
controlled studies, especially for FVC, which was about five times the mean FVC
coefficients from controlled studies. They concluded that the "effective"
exposures in the epidemiclogic studies were cumulative over longer periods
November 21, 1988 49 DRAFT--DO NOT QUOTE OR CITE
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(from 8 to 12 hr versus the 2-hr exposures used to generate the data analyzed
by Hazucha).
No justification was given for the use of the linear model and the
transformation of data from Hazucha (1987), who had used a quadratic model.
At concentrations <100 ppb, a linear model would overestimate lung function
decrements if the quadratic model is more appropriate; while at higher ozone
concentrations it would underestimate lung function decline in comparison to a
quadratic model. Although the range of ozone concentrations in the epidemio-
logic studies reviewed overlap those used in the controlled studies modeled by
Hazucha, the mean concentrations in the respective epidemiologic studies from
which data were used were <100 ppb (see, e.g., Bock et al., 1985; Kinney,
1986).
While asthmatics are not unequivocally more sensitive to ozone than
nonasthmatics, neither have they been shown to be less sensitive (U.S.
Environmental Protection Agency, 1986). Therefore, the findings of a recent
epidemiologic study of asthmatics are included here. Gong (1987) studied the
relationship between air quality and the respiratory status of 83 asthmatics
living in a high-oxidant area of Los Angeles County. The study covered
February to December 1983, but data analysis was limited to a 230-day period
(April 15-November 30) because of staggered entry of subjects into the study
and the high frequency of missing or incomplete data encountered in the earlier
part of the study period.
Regression and correlation analyses between ozone and average symptom
scores, asthma medication index (AMI), and day and night PEFR across subjects
showed weak, non-significant relationships. These daily outcome variables
were compared for days with maximum 1-hr-avg ozone in three ranges: <0.12 ppm;
0.12-0.19 ppm; and >0.20 ppm; "no statistical or clinical significance was
detected." Individual exposures and activity patterns were not estimated in
these two analyses.
Multiple regression analyses also supported the lack of a significant
overall relationship between ozone (and other independent variables) and
respiratory status, despite the use of lagged variables and the inclusion of
other pollutants, meteorological variables, aeroallergens, and AMI. Total
suspended particulates directly affected PEFR but the relationship was not
consistent in the analysis. Aeroallergens showed significantly negative
relationships to respiratory variables, but only the effect of trees was
November 21, 1988 50 DRAFT—DO NOT QUOTE OR CITE
-------
considered clinically relevant. Temperature and humidity showed no signifi-
cant effect on the respiratory variables in this study.
Although there was no significant overall effect of ozone on respiratory
variables in the 83 asthmatic subjects, multiple regression analysis of
subjects whose ozone coefficients on various days were in the top quartile
for dependent variables (respiratory measures) showed significant and consis-
tent effects of ozone on day t and the previous day (t-1). Multiple regression
testing of subsets for associations of symptom score or day or night PEFR on
the same day's ozone and the previous day's value of the same responses showed
highly significant ozone coefficients for all three respiratory measures.
The clinical significance of responses in symptom scores and day and night
PEFR was evaluated for all subjects by individual regression analyses. No
subject had evidence of significant worsening of symptoms attributable to ozone
during the study. Adult subjects with high scores in fatigue, hyperventila-
tion, dyspnea, congestion, and rapid breathing in the Asthma Symptom Checklist
had more negative slope coefficients for ozone than subjects with low-to-
moderate scores on the checklist. "Responders" (statistically identified by
multiple regression analysis) scored consistently higher in the the factors
representing fatigue, hyperventilation, and rapid breathing. The higher scores
of these "responders," however, "were apparently not associated with differ-
ences in ambient ozone concentrations since the test scores were similar during
relatively low (first test) and high (second test) ozone days. The signifi-
cance of the psychological results is unclear at this time and will be the
subject of further analyses" (Gong, 1987).
3.1.3 Laboratory Animal Studies
The recently published and in press reports on the animal toxicology of
03 were evaluated according to their overall relevance to the issues of 0-
toxicology described below. A report not clearly applicable or unique in its
contribution was not considered. Hence, studies that added little or no data
or insight to the issues being addressed, and that corroborated or tended to
duplicate the content of other studies, were eliminated in order to summarize
the newer pertinent data as briefly as possible. New literature has been
selected for review here that contained information on: (1) the effects of
multihour exposures to 0~; (2) the potential health effects of chronic 00
0 3
exposure; and (3) the conceptual and empirical linkages between animal and
November 21, 1988 51 DRAFT—DO NOT QUOTE OR CITE
-------
human 03 toxicology, i.e., extrapolation. Information on a less-specific, but
nevertheless important, aspect of 03 toxicity (e.g., "adaptation") is given
here as well.
3.1.3.1 Effects of Multihour Exposures—Three new studies on the effects in
animals of multihour exposures to 03 (Table 4) have been reported by
researchers at the Dutch RIVM (van Bree et al., 1988; Rombout et al., 1988) and
at the U.S. Environmental Protection Agency (Costa et al., 1988a). Results of
these studies point to the fact that concentration (C) dominates duration of
exposure (T) in eliciting a toxic response to the lung as determined by
lavagable plasma protein on the lung surface. All three studies suggest that
exposure C and T (as well as kill-time in the case of Dutch studies) can be
modeled mathematically and clearly demonstrate the dominance of C in eliciting
effects. Santrock et al. (1988) have shown in mice that products of [18]03
accumulate linearly in the lungs over at least 1 hr of exposure at 1 ppm.
Although the effect of T on response is clearly C dependent, the influence of T
is apparent at all levels with some indication that C and T interact in a
synergistic manner in the low C-long T exposures. While further work on this
last point is needed, it appears that the CxT approach only holds for a given C
and cannot be applied in a general fashion.
The protein and PMN response to repeated 12 hr nocturnal exposures for up
to 3 days as an analogue of an 03 "episode" (van Bree et al., 1988) appeared to
be governed by the initial exposure only. In other words, the degree of
response and recovery time were unaltered by additional exposures during the 2-
or 3-day period. Repeated 2-hr exposures of rats for up to 5 days (Costa
etal., 1988b) resulted in adaptation or attenuation of the (^-induced
functional deficits, with sustained but not worsening protein accumulation
occurring in the lavage. However, the histopathology of these animals appeared
to worsen and evolve from an acute to a more chronic inflammatory pattern.
Recovery or exposure points beyond 5 days were not conducted. Antioxidant
levels of the lung tissues showed a slight upward trend during this period, but
their role in the pattern of response is unclear.
Costa et al. (1988a) have attempted to address whether the apparent
cumulative loss of lung function seen with 03 exposure in human subjects also
occurs in experimental laboratory animals. As reported in humans by Folinsbee
et al. (1988), FVC fell in a linear fashion with estimated cumulative dose
which incorporated ventilation, but;only at lower concentrations (<0.5 ppm for
November 21, 1988 52 DRAFT-DO NOT QUOTE OR CITE
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up to 7 hr). At 0.8 ppm, the effect of T on the C response dramatically
increased as was seen in their matrix studies of CxT relationships and in
similar studies by van Bree et al. (1988). Hence, the impact of T is C
dependent. It should be noted, however, that the apparent cumulative toxicity
of 03 may be endpoint dependent as well and that the simple loss of lung
volume, FVC or FEVp may demonstrate such a relationship (linearity) more
clearly than more interdependent measures such as Dl_co, N2 washout etc.
3.1.3.2 Effects of Chronic Exposure to Ozone—The bulk of the recent reports
on 0- effects in laboratory animals have focused on the structural alterations
of the distal lung associated with prolonged, repeated exposures (see Table 5).
In both the adult and neonate rat (Barry et al., 1988; Grose et al. , 1988;
Huang et al., 1988; Gross and White, 1987) and the monkey (Tyler et al., 1988;
Hyde et al., 1988), high (>0.25 ppm) ambient levels of 03 appear to affect
similarly the junctional airways of the distal bronchioles and the proximal
alveoli. Shifts in cell population occur that result in more cuboidal cells
interfacing the airway lumen, effectively presenting less cell surface to the
air, and presumably reducing individual cell dose Barry and Crapo, 1985; Barry
eta!., 1985, 1988; Sherwin and Richters, 1985). Interstitial inflammation
predominates over time, resulting in thickened septa! areas that do not
completely recover during several weeks of post-exposure clean air (Huang
et al., 1988; Barr et al., 1988; Moffatt et al., 1987). In fact, alternate
months of 03 yielded no difference in ultimate 18-month pathology in monkeys
exposed continually to 0.25 ppm, thereby supporting the observations of a
"smoldering1 persistent lesion (Tyler etal., 1988). These findings are
largely consistent with the reports of enhanced collagen deposition and reduced
turnover with very high ambient levels of 03 (0.57-0.8 ppm) in monkeys (Reiser
et al., 1987) and rats (Hacker et al., 1986; Pickrell et al., 1987), but appear
discrepant with collagen analyses in chronically exposed rats at very 03
concentrations (Filipowicz and McCauley, 1986; Wright etal., 1988) unless
exposure is intermittent (Tyler et al., 1988).
Recently, preliminary reports from the U.S Environmental Protection
Agency's chronic 03 study (Grose et al., 1988) showed that repeated daily
exposure of rats to a daily episodic profile of 03 (22 hr, 0.06 ppm background
with a 0.25 ppm peak; equivalent to a square wave that averaged 0.19 ppm
over 9 hours) for 12 months resulted in small, but significant decrements in
lung function that were consistent with early signs of focal fibrogenesis in
November 21, 1988 54 DRAFT-DO NOT QUOTE OR CITE
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increased total collagen and modest
alveolar ductal fibrosis.
18:2 and 20:4 fatty acids in BAL
increased ~2X in 03 exposed monkeys;
cholesteryl ester levels decreased
and phosphatidylcholine increased
with 90 day exposures. Lung PUFA
levels decreased at 0.15 and 0.30 pp
while plasma LCAT activity increasec
at 0.3 ppm.
ui
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57
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the proximal bronchoalveolar junction (manuscript submitted for publication;
see Chang et a!., 1988). Augmentation of lavagable protein levels and tissue
fractions of ascorbate and glutathione related enzymes after 12 months of 0^
exposure were indicative of the continued oxidant challenge. Further results
of these studies through to 18 months of exposure and with recovery periods are
anticipated by the end of 1988. The functional implications of these altera-
tions in distal airway architecture have been explored in one higher-level 03
study (0.5 ppm) in which airflow mechanics were reversibly altered (Gross and
White, 1987). Lavagable enzymes in rats (Grose et al. , 1988) and lipids in
monkeys (Rao et al., 1985a,b) after prolonged exposures are consistent with
shifting cell populations and/or inflammation, but remain non-specific effects
that still need to be linked with progressive injury or adaptive adjustments to
the challenge.
Initial data have been reported indicating that 0^ has a significant
impact on nasal epithelium and mucosal lining (Harkema et al., 1987a,b). The
health significance of this finding is uncertain, but is consistent with the
deposition data on 0- from both animal and human studies. Hence, though Og is
relatively insoluble in water, the nose appears to provide some degree of
scrubbing, and thus, providing protection to the deeper lung. Species differ-
ences in this capability are an important extrapolation question (see below).
3.1.3.3 Animal-to-Man Extrapolation—Recently reported studies and work in
press cover two aspects of extrapolation: (1) models and their validation,
and (2) species comparisons.
The Miller model (Miller et al. , 1987a,b; Overton et al.> 1987; Miller
and Overton, 1988) of respiratory deposition of 03 has been enhanced with the
incorporation of both ventilatory parameters and empirically derived anatomical
data (see Table 6). Use of the model with input parameters from several rodents
and humans indicates preferential deposition, and presumably associated injury,
in the bronchoalveolar junction which is consistent with empirical findings in
laboratory animals. The model agrees well with the total and partitioned
uptake values determined in human studies (Gerrity et al., 1988), though it
fits less well with the rodent uptake data (Wiester et al., 1988). While the
reasons for this are not as yet clear, the overall consistency of the predicted
deposition distribution within the lung and the approximate equality of dose
rate/surface area suggest that developmental work on the model is progressing
properly (Gerrity and Wiester, 1987).
November 21, 1988 58 DRAFT—DO NOT QUOTE OR CITE
-------
1AN EXTRAPOLATIONS
1
1
— 1
»
ro -^ co
>, C O1
S- OJ tH
rn 1—3 \^v
Hamster is best model for human
antioxidant enzymes.
c
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in eu S- .c
> 1 -P
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S- O) cn
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CZ3 S *— ••
Conclusions are preliminary but
suggest that tissue dosing of
lungs in rats and man may not be
as difficult as might appear on
the basis of total uptake.
01
C S-
ro cu
Total uptake in rats was approxi-
mately 44% of that inspired. Hum
uptake was 96% with 36% uptake in
the nasopharynx. Estimated doses
to lung surface of each species w
about the same assuming nasal
CO
C
i^~ E
i J
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ro ro ro
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ro CO
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Liquid phase reactivity and surf
liquid thickness contribute most
to the 03 tissue absorption rate
and, therefore, to the determina
of local tissue dose and its
regional distribution.
^
•— cu
ro -P co
o ro .c
-P •!— S_ +J
o rn
A mathematical model was used
to quantitatively assess the impai
of physiochemical (solubility,
reactivity, diffusivity radial
air phase transport) and physioloi
variables (lung size, ventilation
on the distribution of 03 dose to
respiratory tract.
i
cu
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ro J3
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r- W T-
Enrichment of 180 in respiratory
tracts of animals exposed to 1803,
more in lining layer than whole
tissue.
in
•P
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ro ro •!-
c^s:
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cn
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ro rH
in *~i
There are species differences
in sensitivity to 03. Mechanism;
not clear but antioxidants are n<
inversely correlated.
BAL protein obtained after 03
were most marked in guinea pigs
(<0.2 ppm). Mice, rats, and
hamsters at <1.0 ppm. Rabbits
at 2.0 ppm. "Not body weight/size
dependent and not comparable in
order of sensitivity to COC12.
o>
1 3
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t 1 •!— tO
csj
1
CM O
cn CM
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ro rH
Approximately 44% of the inhaled
03 was scrubbed by the nose of
rats. Most of the remainder
deposited in the pulmonary regior
Chronic 03 exposure did not
affect uptake.
Total respiratory uptake was
determined by fractional uptake
from inhaled gas. Deposition
distribution in the nose, trachea,
and deep lung were determined for
1S0 distribution in those tissues.
Total uptake was 54%; distribution
was nasopharynx 44%; trachea 7%;
lung 49%. No exposure group
differences.
O)
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(continued on the following page)
59
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TRAPOLATIOHS
S
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at o c c t-
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re in
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H- VI
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Model applied to ht
to BAL protein vali
rodents to compare
response.
in
en ra
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in a
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w e JQ >
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Theoretical model
variety of factors
with deposition in
tract.
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°- £2
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(U C C
1803 used to track
products accumulat
1 hr of exposure a
exponentially duri
exposure.
0)
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as
x: in
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0)
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ratory uptake
basis was abot
ta
rac
alue did not change wi
oncencentration or over
nge of tidal breathing
T
f
v
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r
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O)
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Both human and animal uptake studies of 03 have been conducted (see
Tables 1 and 6). Although humans (Gerrity et al., 1988) appear to retain a
somewhat greater fraction of the inhaled 03 than do rodents (Wiester et al.,
1988), the biological significance of this difference is uncertain at this
time. Santrock et al. (1988) have shown that with continued exposure, products
of 03, as indicated by an [18]0 label, accumulate in the lungs of mice with
continued exposure. The difference in total uptake between humans and labora-
tory rodents may result in part from differences in nasopharyngeal removal of
03 (40% in humans; 17% in rats, as reported by Hatch et al., 1988) resulting
in shifts in regional doses in the two species (surface area differences and
other factors are incorporated). Significant biological variations in lung
tissue concentrations of several antioxidant enzymes have also been reported
(Bryan and Jenkinson, 1987; Slade et al., 1985). How these antioxidants act
individually or collectively as a defense against exogenous oxidants is not
clear, however, since the five animal species tested for 03 toxicity in
concentration-response studies using BAL protein did not show corresponding
variations in their sensitivities (Hatch et al., 1986). Thus, target dosimetry
data, such as that being pursued with [18]0 are needed, along with additional
species sensitivity data to refine this issue. Nevertheless, the ability of
the mathematical model to discern relative species sensitivities is encouraging
despite its evolutionary state (Miller and Overton, 1988). Further work is
still needed, however, to clarify various input components of the model, such
as the roles of reactive surface fluid components and regional ventilation, for
example, thereby ensuring its continued refinement and applicability to the
extrapolation issue (Hanna et al., 1988).
3.1.3.4 Related Studies—An animal model has been developed (Costa et al. ,
1988b) that exhibits the same pattern of attenuated response to intermittent
short-term QS (a phenomenon known as "adaptation") as has been described in
man (see Table 7). This model demonstrates that morphological and biochemical
changes continue even while lung dysfunction attenuates with repeated 0-,
exposure, suggesting that the use of lung function tests alone to assess injury
can result in misinterpretation of risk to health with repeated exposures to
03. This does not rule out biological attenuation over a longer time period,
but simply points out the gap in our knowledge in relating acute to chronic
injury. Recently, Nikula et al. (1988a,b) showed that after 60 days (8 hr/
night) of exposure to 0.96 ppm QS rat trachea! explants were significantly more
November 21, 1988 61 DRAFT-DO NOT QUOTE OR CITE
-------
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resistant to the tissue necrosis produced by 3.0 ppm 0, than were naive
O
trachea! explants, suggesting that chronic "adaptation/tolerance" may in fact
be real.
3.2 SUMMARY AND CONCLUSIONS: NEW HEALTH EFFECTS DATA
The following statements may be made on the basis of the preceding review
of the newer health effects data now available.
1. Newer data from 1- and 2- hr controlled studies (Avol et al.,
1987; Linn et al. , 1986) add to existing concentration-response
data indicating that lung function decrements and respiratory
symptoms occur in children and young adults exposed for 1 to
2 hr to low 03 concentrations ranging from 0.12 to 0.16 ppm
while performing moderate to heavy exercise. Explanations for
differences in lowest-observed-effects-levels among individuals
and among cohorts include subject characteristics, exposure
histories of subjects, and possible but presently unidentified
differences in actual controlled exposure conditions.
2. In controlled studies, older subjects (>50 yr old) appear to
have smaller changes in lung function than younger subjects when
exposed to similar ozone concentrations (Bedi et al., 1988; Bedi
and Horvath, 1987; Drechsler-Parks et al., 1987, 1988; Reisenauer
etal., 1988). There were no significant differences between
the responses of men and women to 03 exposure for FEV-, and FVC,
although women had a significant increase in total respiratory
resistance (Reisenauer et al., 1988). Since women had slightly
lower mean exercise V£ during the studies, the data suggest that
women may be somewhat more responsive to 03 than men (Dreshsler-
Parks et al., 1987; Reisenauer et al., 1988). The responses to
03 may be less reproducible, however, in older than in younger
adults (Bedi et al., 1988).
3. In more recent studies of adults with and without asthma (Kreit
et al., 1988; Eschenbacher et al., 1988), both groups experienced
similar responses to 0.4 ppm 03 exposure, as indicated by
decrements in standard spirometric pulmonary function tests and
airway responsiveness to methacholine, but the changes were
greater in asthmatics. Specific airway resistance was not
increased in nonasthmatics, but in asthmatics nearly twice the
increase was seen after exercise in 03 versus air exposures. No
symptom differences were seen between adult asthmatics and
nonasthmatics. Pre- and post-ozone exposure challenge with
methacholine may have confounded the results, however. Responses
were also similar for adolescent asthmatics and nonasthmatics
exposed to 0.12 and 0.18 ppm 03 (Koenig etal., 1987, 1988),
although a small but significant increase in FEF(-nr was observed
in asthmatics after 0.12 ppm 03 exposure. In the* fdult nonasth-
matics studied by Eschenbacher et al. (1988), indomethacin
November 21, 1988 63 DRAFT—DO NOT QUOTE OR CITE
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pretreatment blocked the restrictive but not the airway
reactivity component of the effects of 03; a placebo effect was
also observed in these nonasthmatics. A study by McDonnell
et al. (1987) indicates that adults with allergic rhinitis show
similar airway responsiveness to histamine after exposure to
0.18 ppm 03 as a comparable group of nonallergic subjects. The
only difference was a significant increase in airway resistance
in the allergic subjects. It appears, therefore, that both
allergic and asthmatic subjects have a greater increase in
airway resistance after ozone exposure than do healthy subjects.
The apparent order of airway responsiveness to 03 from these
studies is normal 80 L/min) for 1 hr at 03 concentrations >0.18 ppm,
but not at 0.12 ppm. Data from a third study (Linder et al.,
1988) suggests that small decrements in maximal exercise perfor-
mance may occur at 03 concentrations <0.18 ppm, but limitations
and questions concerning this study require further verification
of the results. Environmental conditions such as high ambient
temperature and/or relative humidity may affect subjective
symptoms and may independently impair exercise performance such
that differentiation between 03-induced effects and effects of
other environmental conditions may be difficult.
6. Controlled human studies of prolonged exposure (for up to
6.6 hr) to low 03 concentrations ranging from 0.08 to 0.12 ppm
report progressively larger pulmonary decrements and increased
respiratory symptoms with increasing duration of exposure at
moderate exercise levels (VF = 40 L/min) (Folinsbee etal.,
1988; Horstman et al., 1988afb). They are similar in magnitude
to those previously reported for healthy subjects performing
heavy exercise (\L >60 L/min) in high 03 concentrations
(>0.2 ppm) for shorter durations (~2 hr).
November 21, 1988 64 DRAFT—DO NOT QUOTE OR CITE
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7. New data show inflammatory and biochemical changes from expo-
sures to moderately high .levels (0.40 ppm) of 03 for 2 hr with
intermittent exercise (V^ = 70 L/min), as determined from
bronchoalveolar lavage CBAL) 18 hr post-03-exposure (Koren
etal., 1988a,b,c,d). Cells and enzymes capable of causing
damage to pulmonary tissues, along with proteins involved in
fibrotic and fibrinolytic processes, were increased at 18 hr
post-exposure. Also, evidence of increased epithelial per-
meability (as determined by clearance of 99mTc-DPTA) was
observed (Kehrl etal., 1987). Preliminary findings have
been reported (Koren etal., 1988b) of elevated PMNs, also
determined by BAL, in subjects exposed 6.6 hr to low levels of
03 (0.1 ppm). Whether inflammation occurs following multihour
exposures to lower 03 levels remains unknown, but studies
designed to determine this are now in progress.
8. Newer studies related to the dosimetry of 03 show that
differences in mode of breathing do not produce appreciable
differences in fractional uptake of 03 in the respective regions
of the human respiratory tract. Increased frequency of breath-
ing results in a decreased fractional removal of 03 in both the
upper (URT) and the lower respiratory tract (LRT), possibly as
the result of decreased residence time in the airways and
increased flow rate. The lowest fractional removal of 03 in the
URT occurred during nasal breathing, so that shifts from nasal
to oronasal breathing resulting from exercise would somewhat
offset increases in delivered dose caused by increased breathing
frequency (Gerrity etal., 1988). Ozone-induced changes in
tidal volume during 60-min, continous-exercise (VV = 40 L/min)
exposures to 0.4 ppm resulted in a slight reduction in total 03
uptake (4%) and a larger reduction in LRT ozone uptake (9%).
Thus, the typical ozone-induced reduction in tidal volume may
protect the lower airways, with possible loss of that protection
with recovery of normal tidal volume (Gerrity and McDonnell,
1988). Increased flow rates appear to reduce nasopharyngeal
uptake (Gerrity, 1987). Additional modeling is need, however,
to determine the effects of heavy exercise on regional dosime-
try, especially on 03 uptake in the LRT. These recent
dosimetric data indicate that dosimetry modeling has progressed
well in the past year or so. Additional data are still needed
in other areas important to animal-to-man extrapolation,
namely, tissue sensitivity and relative species sensitivities.
9. Newer epidemiological studies have employed numerous refinements
over some of the older studies, in the form of: (a) better
estimates of exposure, not just to ozone but also to other
pollutants and other environmental variables that can confound
or otherwise influence the outcome (e.g., Bates and Sizto, 1987;
Spektor etal., 1988a,b; Raizenne etal., 1987); (b) use of
serial measurements of pulmonary function for determining
correlations with pollutants and other environmental variables
(e.g., Raizenne etal., 1987, 1988; Spektor etal., 1988a,b);
and (c) better biomedical characterization of cohorts (e.g.,
Raizenne et al., 1987, 1988; Gong et al., 1988).
November 21, 1988 65 DRAFT--DO NOT QUOTE OR CITE
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10. Despite their refinements, however, newer epidemiologic studies
have produced mixed results regarding the possible role of ozone
versus the roles of other agents or factors in eliciting the
functional decrements and/or rates of respiratory symptoms or
respiratory disease observed. While functional decrements and
respiratory symptoms have been shown in a number of studies to
be statistically associated with ozone, other studies have shown
them to be wholly attributable to particles (e.g., Dockery
etal., 1988); or partially attributable to particles (e.g.,
Kinney, 1986); or partially attributable to other environmental
factors such as ambient temperature or humidity (e.g., Spektor
etal., 1988a) or even aeroallergens (e.g., Dockery etal.,
1988; Gong et al., 1987).
11. Respiratory symptoms in epidemiologic studies have been reported
not to occur in association with 03 more often than such an
association has been reported. Studies in which symptoms have
not been reported at all following short (1-hr to multihour)
daily exposures (over multiple days to multiple months) to
ambient air containing ozone include (a) studies of children
attending day or residential camps (Raizenne et al., 1987, 1988;
Spektor et al., 1988a); (b) at least two panel studies (Dockery
et al., 1988; Veda! et al., 1987); and (c) a study of adults
exercising outdoors nearly every day (Spektor et al., 1988b). A
recent reanalysis, using more widely accepted statistical
approaches (Schwartz et al. , 1988) of the Hammer et al. (1974)
panel study of nurses in Los Angeles showed that cough was
associated with 03, but only at relatively high levels (well
above 0.12 ppm). In a panel study of asthmatics (Gonga 1987),
respiratory symptoms occurred during the study but did not
correlate significantly with ozone overall and no worsening of
symptoms attributable to 03 occurred. (Multiple regression
analysis of responses of those asthmatics in the top quartile
for respiratory measures showed relationships between the
respiratory measures and 03, but these associations showed no
dose-response pattern (Gong, 1987).)
12. Data reported from some of the newer epidemiologic studies show
pulmonary function decrements that are as large or larger than
those observed in human controlled (chamber) studies. Investi-
gators have attributed these larger decrements as indicating,
variously: (a) cumulative effects of 03 occurring as the result
of multihour exposures; (b) interactive effects of co-pollutants
(additive or synergistic effects); (c) interactive or possibly
independent effects of other environmental factors;
(d) misspecification of true exposures, either because of
inadequate dosimetry or other inadequacies in exposure charac-
terization; and (e) possible persistence of effects from one day
to the next.
13. Data showing such functional decrements have been reported in
some recent studies (e.g., Raizenne et al., 1987, 1988; Spektor
et al., 1988a,b; Kinney et al. , 1988) in a manner intended to
facilitate comparison of these decrements with those observed in
November 21, 1988 66 DRAFT—DO NOT QUOTE OR CITE
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chamber studies. While it does permit easier comparison of
epidemiologic findings with chamber-study data, this method of
reporting also raises several questions that EPA believes must
be investigated further before such findings can be taken at
face value. Data on functional decrements have been reported as
-ml/ppb 03 for measures such as FEV^o and FVC; and as
-ml/sec/ppb for measures such as PEF and MMEF. Expression of
data in this form assumes that: (a) 03-induced changes in
respiratory function are linear across all concentrations
encountered in these studies (from zero up through episodic
levels); and (b) the relationships among C, T, and VF do not
change with variations in these respective components of
exposure. These assumptions are open to question. For
example, the relationships between respiratory function changes
and the respective components of exposure--C, T, and VF --have
not been tested at concentrations <0.08 ppm in chamber studies;
and data obtained in chamber studies at the lowest concentration
used (0.08 ppm) have not been modeled to determine whether
changes in the influence of respective components are monotonic
across ranges of C, T, or VF . Furthermore, questions of
nonlinearities in the respective effects of C, T, and VF on
ozone-induced pulmonary function changes are far from resolved.
In Kinney et al. (1988), data from controlled (chamber) studies
modeled by Hazucha (Hazucha, 1987; U.S. Environmental Protection
Agency, 1986) were transformed and compared with data from five
epidemiologic studies. The transformation assumed the applica-
bility of a linear model even though Hazucha had fit data from
controlled (chamber) studies to a quadratic model in^describing
changes in pulmonary function as a function of VF . Mean
concentrations in the five epidemiologic studies were lower than
the lowest concentration used in the controlled studies modeled.
14. In most of the epidemiologic studies, the collinearity of
temperature and 03 concentrations continues to cloud interpre-
tation of study results. An additional factor confusing
interpretation of epidemiologic results is the collinearity
between exercise and total dose; i.e., exercise increases the
total dose of ozone delivered to the respiratory tract and
therefore the effects of exercise versus the effects of ozone
dose are difficult to separate in epidemiologic studies.
Subjects in chamber studies are usually better characterized
before being studied than subjects in recent epidemiologic
studies, who have generally been characterized by respiratory
questionnaires but seldom by bronchial challenge or skin tests.
Given the finding of apparently 03-associated decrements in PEFR
in some of the more recent studies, additional subject charac-
terization to eliminate or reduce confounding by exercise-
induced bronchospasm would be useful and would clear up some
existing questions about the weight that can be placed on
epidemiologic data that appear to be quantitatively consistent
with chamber studies of 1-hr to multihour duration.
November 21, 1988 67 DRAFT—DO NOT QUOTE OR CITE
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15. Three new studies on the effects in laboratory animals of
multihour exposures to 03 (Rombout et a!., 1988; van Bree
et a!., 1988; Costa et a!., 1988) report that exposure concentra-
tion (C) dominates duration of exposure (T) in eliciting 03-
induced changes in lavagable protein and antioxidant enzyme
levels. Preliminary modeling efforts describing this data
suggest that CxT interaction (synergism) occurs at decreased C
and increased T; however, CxT relationships can only be applied
at a given C and cannot be applied in general. The time of day
of exposure is also an important determinant of oxidant toxicity
since nocturnal exposures cause greater responses than do
diurnal exposures. The primary determinants of 03 toxicity are,
therefore, exposure concentration and time of exposure followed
by the duration of exposure.
16. New studies in monkeys and rodents support earlier findings that
prolonged, repeated exposure to high concentrations of 03
(>0.4 ppm) lead to the development of peri bronchiolar inflamma-
tion (Barr et al., 1988; Moffatt et al., 1987), increased lung
collagen content (Reiser etal., 1987; Pickrell et;al.5 1987;
Hacker etal., 1986), and lung function changes (Gross and
White, 1986, 1987). Even at lower 03 concentrations (0.12 to
0.30 ppm), a lesion is still evident at the junction of the
conducting airways and the gas exchange regions of the lung,
characterized by cell population shifts along with interstitial
inflammation and thickening (Huang etal., 1988; Barry and
Crapo, 1985; Barry etal., 1985, 1988; Sherwin and Richters,
1985) but without increased lung collagen content (Wright
et al., 1988; Filipowicz and McCauley, 1986) unless exposure is
intermittent (Tyler etal., 1988). Preliminary information
(Grose etal., 1988) from "episodic" exposure (0.19 ppm
average concentration of 03 over 9 hrs) of rats for 12: months
indicates that significant decrements in lung function also
occur at these lower 03 concentrations that are consistent with
early signs of focal fibrogenesis in this region of the lung.
Increased lavagable lipids in monkeys (Rao etal., 1985a,b)
found after prolonged exposure to ambient levels of 03 (0.15 to
0.30 ppm) are also consistent with the shifting cell populations
and/or inflammation reported at these concentrations. Multiple
exposures to ambient levels of 03 (0.15 and 0.30 ppm, 8 hr/day
for 6 or 90 days) also cause injury and cellular changes in
transitional and respiratory epithelium of the nose of rionhuman
primates (Harkema et al., 1987a,b; Hyde et al., 1988).
17. Mathematical dosimetry models indicate preferential deposition
of 03 in the bronchoalveolar junction that is consistent with
known laboratory animal data (Miller and Overton, 1988; Miller
et al., 1987a,b; Overton et al., 1987). Further work is needed,
however, to clarify various input components of the models, such
as the roles of reactive surface fluid components and regional
ventilation, for example, thereby insuring its continued refine-
ment and applicability to the extrapolation issue (Hanna et al.,
1988). Humans appear to retain a greater fraction (95%) of
inhaled 03 than do rodents (50%) but tissue dose rates/surface
November 21, 1988 68 DRAFT—DO NOT QUOTE OR CITE
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area in each species may not be that different if nasopharyngeal
partitioning is considered (Wiester et al. , 1987, 1988; Gerrity
and Wiester, 1987; Gerrity, 1987). Target dosimetry data, such
as that being conducted with [18]03 (Hatch et al., 1988;
Santrock et al., 1988; Aissa and Hatch, 1988; Hatch and Aissa,
1987) are needed, along with species sensitivity data (Bryan and
Jenkinson, 1987; Hatch eta!., 1986; Slade eta!., 1985) to
better refine this issue.
18. Laboratory animals exhibit a similar pattern of attenuated
response to intermittent, short-term exposure as has been
described in man (Costa etal., 1988b). Morphological and
biochemical changes, however, even occur while lung dysfunction
attenuates with repeated 03 exposure, suggesting that the use
of lung function tests alone to assess 03-induced lung injury
may result in misinterpretation of risk to the health of
exposed individuals. More research is needed, therfore, to
improve our knowledge of relationships between acute and
chronic lung injury.
4. BIBLIOGRAPHY
4.1 VEGETATION REFERENCES
Adomait, E. J.; Ensing, J.; Hofstra, G. (1987) A dose-response function for the
impact of 03 on Ontario-grown white bean and an estimate of economic loss.
Can. J. Plant Sci. 67: 131-136.
*Amundson, R. G. ; Kohut, R. J. ; Schoettle, A. W. ; Raba, R. M.; Reich, P. B.
(1987) Correlative reductions in whole-plant photosynthesis and yield of
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*Amundson, R. G. ; Raba, R. M. ; Schoettle, A. W.; Reich, P. B. (1986) Response
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*Brennan, E. ; Leone, I.; Greenhalgh, B. ; Smith, G. (1987) Chlorophyll content
of soybean foliage in relation to seed yield and ambient ozone pollution.
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*Brennan, E. ; Harkov, R. S. (1987) Comment on "regional tree growth reductions
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Technol. 21: 606-607.
*Cooley, D. R. ; Manning, W. J. (1988) Ozone effects on growth and assimilate
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with different characterizations of the same ozone treatments. J. of
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69
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*Eberhardt, J. C.; Brennan, E. ; Kuser, J. (1988) The effect of fertilizer
treatment on ozone response and growth of eastern white pine. J.
Arboricul. 14: 153-155.
*Ensing, J.; Hofstra, G.; Adomait, E. J. (1986) The use of cultivar yield data
to estimate losses due to ozone in peanut. Can. J. Plant Sci. 66: 511-520.
*Ensing, J.; Hofstra, G.; Roy, R. C. (1985) The impact of ozone on peanut
exposed in the laboratory and field. Phytopath. 75: 429-432.
*Heagle, A. S.; Flagler, R. B. ; Patterson, R. P.; Lesser, V. M. ; Shafer, S. R.;
Heck, W. W. (1987) Injury and yield response of soybean to chronic doses
of ozone and soil moisture deficit. Crop Sci. 27: 1016-1024.
Heagle, A. S.; Heck, W. W.; Lesser, V. M.; Rawlings, J. 0. (1987) Effects of
daily ozone exposure duration and concentration fluctuation on yield of
tobacco. Phytopath. 77: 856-862.
*Heagle, A. S.; Heck, W. W.; Lesser, V. M.; Rawlings, J. 0.; 'Howry, F. L.
(1986) Injury and yield response of cotton to chronic doses of ozone and
sulfur dioxide. J. Environ. Qua!. 15: 375-382.
Heagle, A. S.; Lesser, V. M. ; Rawlings, J. 0.; Heck, W. W. ; Philbeck, R. B.
(1986) Response of soybeans to chronic doses of ozone applied as constant
or proportional additions to ambient air. Phytopath. 76: 51-56.
*Heck, W. W.; Dunning, J. A.; Reinert, R. A.; Prior S. A.; Rangappa, M. ;
Benepal, P. S. (1988) Differential responses of four bean cultivars to
chronic doses of ozone. J. Amer. Soc. Hort. Sci. 113: 46-51.
*Heggestad, H. E.; Bennett, J. H.; Lee, E. H.; Douglas, L. W. (1986) Effects of
increasing doses of sulfur dioxide and ambient ozone on tomatoes: Plant
growth, lead injury, elemental composition, fruit yields, and quality.
Phytopath. 76: 1338-1344.
Hogsett, W. E.; Tingey, D. T.; Lee, E. H. (1988) Ozone exposure indices:
Concepts for development and evaluation of their use. In: Assessment of
Crop Loss'from Air Pollutants, pp. 107-138. W. W. Heck, 0. C. Taylor and
D. T. Tingey (eds.). Elsevier Applied Science, New York.
*Holley, J. D.; Hofstra, G.; Hall, R. (1985) Effect of reducing oxidant injury
and early blight on fresh weight and tuber density of potato. Phytopath.
75: 529-532.
*Kats, G.; Dawson, P. J. ; Bytnerowicz, A.; Wolf, J. W. ; Thompson, C. R. ;
Olszyk, D. M. (1985) Effects of ozone or sulfur dioxide on growth and
yield of rice. Agri. Ecosys. Environ. 14: 103-117.
Kohut, R. J.; Laurence, J. A.; Colavito, L. J. (1988) The influence of ozone
exposure dynamics on the growth and yield of kidney bean. Environ. Poll.
53: 79-88.
*Kohut, R. J. ; Amundson, R. G.; Laurence, J. A.; Colavito, L. ; Van Leuken, P.;
King, P. (1987) Effects of ozone and sulfur dioxide on yield of winter
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November 21, 1988 70 DRAFT—DO NOT QUOTE OR CITE
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*Kohut, R. J.; Amundson, R. G.; Laurence, J. A. (1986) Evaluation of growth and
yield of soybean exposed to ozone in the field. Environ. Pollut. (Series
A) 41: 219-234.
*Kress, L. W.; Miller, J. E. ; Smith, H. J.; Rawlings, J. 0. (1986) Impact of
ozone and sulphur dioxide on soybean yield. Environ. Pol. 41: 105-123.
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system for interrelating effects, standards, and needed source reductions:
Part 7. An 03-S02 leaf injury mathematical model. J. Air Pollut. Control
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for
8. An
Larsen, R. I.; Heck, W. W. (1984) An air quality data analysis system foi
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Control Assoc. 34: 1023-1034.
Larsen, R. I.; McCurdy, T. R.; Johnson, P. M.; Heck, W. W. (1989) An air
quality data analysis system for interrelating effects, standards, and
needed source reductions: Part 10. Potential ambient 03 standards to limit
soybean crop reduction. J. Air Pollut. Cont. (In Press).
Lee, E. H. ; Tingey, D. T.; Hogsett, W. E. (1987) Selection of the best
exposure-response model using various 7-hour ozone exposure statistics.
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Quality Planning and Standards, Research Triangle Park, N.C. 27711.
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indices in exposure-response modeling. Environ. Pollut. 53:43-62.
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Lefohn, A. S. ; Laurence, J. A.; Kohut, R. J. (1988a) A comparison of indices
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Lefohn, A. S. ; Laurence, J. A.; Kohut, R. J. (1988b) A comparison of indices
that describe the relationship between exposure to ozone and reduction in
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*Marie, B. A.; Ormrod, D. P. (1986) Dose-response relationships of the growth
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Musselman, R. C.; Huerta, A. J.; McCool, P. M.; Oshima, R. J. (1986) Response
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*01szyk, D. M.; Bytnerowicz, A.; Kats, G.; Dawson, P. J.; Wolf, J.; Thompson,
C. R. (1986) Effects of sulphur dioxide and ambient ozone on winter wheat
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*Peterson, D. L.; Arbough, M. J.; Wakefield, V. A.; Miller, P. R. (1987)
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synthesis in tree and crop species. Science 230: 566-570.
*Reich, P. B.; Schoettle, A. W.; Raba, R. M. ; Amundson, R. G. (1986) Response
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Atmos. Environ. 22: 1224-1242.
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Tingey, D. T. ; Hogsett, W. E. ; Lee, E. H. (1988) Analysis of crop loss for
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*Wang, D. ; Bormann, F. H. ; Karnosky, D. F. (1987) Comment on "regional tree
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^Reviewed but not used in summary because data are not pertinent to averaging-
time of secondary NAAQS; or no new data are presented.
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4. BIBLIOGRAPHY
4.2 HEALTH REFERENCES
Adams, W. C.; (1987) Effects of ozone exposure at ambient air pollution
episode levels on exercise performance. Sports Med. (Auckland) 4: 395-424.
Aissa, M.; Hatch, G. E. (1988) Method for tracing oxygen 18 in vivo: applica-
tion to ozone dosimetry in animals. In: Oxygen radicals in biology and
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Avol, E. L.; Linn, W. S.; Shamoo, D. A.; Spier, C. E.; Valencia, L. M.; Venet,
T. G.; Trim, S. C.; Hackney, J. D. (1987) Short-term respiratory effects
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November 21, 1988 83 DRAFT—DO NOT QUOTE OR CITE
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