presumably by such defensive mechanisms as increased mucus secretion,
epithelial mitesis, and enzyme induction (64). Because the inflammatory
responses in the airway are considered to be, in some measure, protective,
it has been questioned whether or not adaptation is a good thing (65).

RECOMMENDATIONS

In brief, this review/update does not reveal that earlier findings need to
be corrected, except that, in a few experiments, subjective responses
(respiratory irritation) in heavily exercising humans have been shown at
levels of ozone as low as 0.12 ppm. There is, however, no strong evidence
pointing to the need for review or revision of existing FAA ozone standards.
The implication of a neurological component in the early response to ozone
is interesting and significant and should be investigated further.

il


While the rule may have stilled most expressions of concern about cabin
ozone, not much research has been reported as yet to tell how effective
ozone scrubbing in airliner cabin air really is. The National Research
Council's Committee on Airliner Cabin Air Quality has recommended that
the FAA establish policies for periodic removal and testing of ozone-
scrubbing catalytic filters to establish the effective life of these units (7).
The committee further recommended that a program of on-board, in-flight
monitoring be established so that compliance with the rule could be
assured. The FAA has responded by contracting with a private research
organization .to carry out extensive monitoring of cabin ozone
concentrations during commercial airline flights.

To review briefly for perspective, upper air ozone is one product in a
complex cycle of photochemical reactions (8). Ozone is formed from
biatomic oxygen acted upon by solar ultraviolet radia:ion with a
wavelength of less than 242 nm, thus:

1. 02 + bv ------ >0+0

In the high atmosphere:

Where M is any body, most commonly nitrogen.
3. 03 + hv ------ > 02 + O*

Where 0* is an electronically excited oxygen atom ‘hat can enter into a
destructive reaction with ozone, thus:

4. 03 + 0* ------> 2 07

This latter reaction destroys about 20 percent of the ozone continuously
formed in reaction 2. The “hydrogen system" destroys another 10 percent
of the ozone formed in 2, thus:

5. H20 +0* -—---> 2 HO

The following reactions are more important at altitudes above 40,000
meters (>130,000 feet) than at lower altitudes:

6. HO + 03 ------ > H02 + 02



4l.

42.

43

44.

4s.

46.

47.

48.

49,

50.

Pryor, W. A. “Oxy-Radicals and Related Species: Their Formation, Lifetimes and
Reactions.” Ann. Rev. Physiol. 48:657 - 667, 1986.

Dubick, M. A., S. Zidenberg-Cherr, R. B. Rucker and C. L. Keen. "Superoxide
Dismutase Activity in Lung From Copper and Manganese-Deficient Mice
Exposed to Ozone." Toxicology Lett. 42:149 - 157, 1988.

. Calabrese, E. J., G. S. Moore and P. B. Williams. "Effect of Mcthy] Oleate Ozonide, a
Possible Ozone Intermediate, on Normal and Glucose 6-Phosphate
Dehydrogenase-Deficient Erythrocytes." Env. Contam. and Tox. 29 : 498 - 504,
1982,

Bhalla, D. K., S. M. Lavan and T. T. Crocker. "Airway Permeability in Rats Exposed to
Ozone or Treated with Cytoskeleton-Destabilizing Drugs." Exp. Lung Res.
14:501 - 525, 1988.

van Bree, L., H. P. Haagsman, L. M. G. van Golde and P. J. A. Rombout.
“Phosphatidylcholine Synthesis in Isolated Type II Pneumocytes from Ozone-
Exposed Rats." Arch. Tox. 61:224 - 228, 1988.

Alink, G. M., R. M. de Boer, J. Mol and J. H. Temmink. "Toxic Effects of Ozone on
Human Cells In Vitro, Exposed by Gas Diffusion through Teflon Film.”
Toxicology 17:209 - 218, 1980.

Driscoli, K. E. and R. B. Schlesenger.” Alveolar Macrophage-Stimulated Neutrophil
and Monocyte Migration: Effects of Jn Vitro Ozone Exposure.” Toxicol. and
Appl. Pharm. 93:312 - 318, 1988.

Goldstein, B. D. and E. M. McDonagh. "Effects of Ozone on Cell Membrane
Fluorescence." Envy. Res. 9:179 - 186, 1975.

Johnson, D. A. "Ozone Inactivation of Human Alpha 1-Proteinase Inhibitor.” Am.
Rev. Resp. Dis. 121:1031 - 1038, 1980

. Jones, G. L., C. G. Lane, E. E. Daniel and P. M. O'Byrne. "Release of Epithelium-
Derived Relaxing Factor after Gzone Inhalation in Dogs.” J. Appl. Physiol.:
Respirat. Environ. Exercise Physiol. 65:1238 - 1243, 1988.

51. Rabinowitz, J. L. and D. J. P. Bassett. "Effect of 2.0 ppm Ozone Exposure on Rat Lung

52.

53.

54.

Fatty Acids." Exp. Lung Res. 14:477 - 489, 1988.

Roycroft, J. H., W. B. Cunter and D. B. Menzel. "Ozone Toxicity: Hormone-Like
Oxidation Products from Arachidonic Acid by Ozone-Catalyzed Autooxidation.”
Toxicol. Lett 1:75 - 82, 1977.

Wong, D. S. and P. Hocastein. "The Potentiation of Ozone Toxicity by Thyroxine."
Res. Comm. Chem. Pathol. Pharmacol. 31:482 - 492, 1981.

L. 3. Machlin and A. Bandich. “Free Radical Tissue Damage: Protective Role of
Antioxidant Nutrients." FASEB Jour. 1:441 - 445, 1987.

15



Czone still has not been shown convincingly to have any primary
extrapulmonary effects. Gliner et al. (32) failed to show an effect of ozone
(0.75 ppmv) on the human EEG.

Many papers have appeared in the recent literature regarding the site
and mechanism of oxidant-induced damage. An interesting feature of some
of these studies is the involvement of the parasympathetic nervous system
in the early response of the airway to ozone. Gertner et al. (33, 34) studied
the resistance in dogs’ peripheral lung by way of a bronchoscope wedged in
a segmental airway. Exposure of the lung segment to 1.0 ppmv ozone
caused an increase in resistance of the lung collateral system (Rcs) in 2 min,
which was prevented by bilateral vagotomy. Vagetomy, however, did not
prevent a later increase in Res that was reduced by chlorpheniramine.
There was no development of adaptation or tolerance to 1.0 ppmv as had
been shown to occur with 0.1 ppmv. These workers interpreted their
findings to mean that the early bronchoconstrictive response was mediated
by the parasympathetics and the later congestive response by histamine.
These investigators later showed that the lung response to histamine
aerosols was increased by 1.0 ppmv ozone. Jones and associates (35) took
strips of trachealis muscle from dogs that had shown hyper-responsiveness
to ozone. The strips were studied in vitro for responsiveness to electric fieid
stimulation, acetylcholine and potassium chloride. Excitatory junction
potentials were measured with microelectrodes to determine if inhaled
ezone affects acetylchcline release from parasympathetic nerve endings.
Provocative doses of acetylcholine dropped from 4.11 mg/ml without ozone
to 0.66 mg/ml with ozone. Electric field responsiveness was increased but
not so with potassium chloride. The authors suggest that a postjunctional
alteration in trachealis smooth muscle results from ozone exposure and
accounts for subsequent airway hyper-responsiveness. Barry and associates
(36) showed morphometrically that terminal bronchicies of the rat were
particularly susceptible to low levels of ozone ( 0.25 ppmv), producing 20
to 30 percent loss of cilia; luminal surfaces of Clara cells were reduced by
16 to 25 percent. Dubick et al. (37) showed that young monkeys exposed to
0.25 ppmv ozone for 8 h/d on alternate months had significantly increased
lung collagen content, chest wall compliance, and inspiratory capacity. All
had_ bronchiolitis.

In human subjects, bronchioalveolar lavage of lungs of young men
exposed earlier for 2 h to 0.4 ppmv ozone showed an 8.2-fold increase in
percentage of polymorphonuclear leucocytes, with a small decrease in
percentage of macrophages (38). Immunoreactive neutrophil elastase, often
associated with inflammation and lung damage, increased 3.8-fold in the
lavaged fluid and 20.6-fold in iavaged cells. Increased vascular



12. 02 +M ------ >0+0+M

O+N) ------ >N+NO

The reraainder of the ozone formed from 02 _ is destroyed by other
systems, such as chlorine, sulfur, and man-made _ products--mainly
chlorofluoromethanes and carbon tetrachloride (natural and man-made).
The consensus is that the sum of destructive reactions presently exceeds
synthetic ones so that stratospheric ozone levels are falling. Of course, all
other constituents of the ozone cycle are also compressed into airliner cabin
air, though their contributions as contaminants have apparently not been
reported and are probably negligibie.

Ozone levels naturally vary with latitude, altitude, and season of the
year. Ozone concentration seems to be maximal in the atmosphere between
20,000 and 90,000 feet, the so-called ozone layer; present-day airliners
normally operate in the lower to middle part of this iayer (9).

Ozone levels have been measured in cabin air in a few instances. Brabets
(10) reported that many (unspecified number) passengers on commercial
jet airliners stated that the odor of ozone was detectable at flight altitudes
of 30,000 to 40,000 feet. Ozone measuremeats were made during 285
flights covering the 48 contiguous states and Alaska and five flights from
California to Hawaii. Concentrations ranging from 0.01 to 0.40 ppmv were
found on half of the flights with the highest level occurring on a flight from
Anchorage to New York. No differences were found, on the average,
between cabin and cockpit ozone levels, although cabin values fluctuated
less than the cockpit values because of the larger cabin volume.

Briehl and Perkins (11) simultaneously measured outside air and cabin
air ozone in a Gates Learjet at altitudes up to 42,500 feet on six flights in
February 1978. Peak concentration was 0.41 ppmv and cabin ozone
decreased in proportion to the number of passengers, amount of luggage,
etc. in the cabin. Ozone concentration near the cabin air vents was only
slightly reduced from the outside air ozone concentration. Cabin air levels
followed but lagged behind atmospheric ozone by about 54 seconds;
therefore, it was difficult to know the cabin ozone retention value when
atmospheric ozone was changing rapidly. Generally, cabin ozone levels were
about 50 percent (47 to 60 percent) of atmospheric levels. The maximum
atmospheric ozone level encountered was 0.89 ppmv.

Holdeman and Nastrom (12) and Perkins Holdemaa and Nastrom (13)
have reported results from the Global Air Sampling Program (GASP) of


H02 + 0 ------ > OH + 02

Thus, converting one ozone molecule and one atom of oxygen into two
molecules of biatomic oxygen. The catalyst, OH, is renewed to re-enter the
reaction with 063 formed in 2. OH radicals can also appear in the

stratosphere from upwardly-diffusing methane formed by ground
generators such as marshes and swamps and react thus:

7. CHg + 0* ------ > CH3 + OH

The perhydroxyl radical (HO2) formed in 6, above, reacts with OH to
produce water, which can drift down into the lower atmosphere.

8. OH + H02 ------ > H20 + 02

The "Nitrogen System” is principally responsible for maintaining ozone
balance in the stratosphere and consists mainly of N20 released at the

earth's surface by micro-organisms in the oceans and soil, which diffuse
into the stratosphere where reactions with UV and O occur, thus:

9. N20 + 0* ------ >2NO

NO2 + hv ------ >NO+0
Nitric oxide, NO, breaks down ozone, thus:

16. NO + 03 ------ > N02 + 02
HO2 + 02 ------> NO + 2 02
transforming ozone into biatomic oxygen. Finally, NO2 is removed:

11. OH + NO2 + M -----> HNO3 +M

Nitric acid is washed out of the upper atmosphere and is the major sink
of the cyciic system. Almost 60 percent of the ozone formed is destroyed in — ow
this way. NO2 in the upper atmosphere is increased by the use of nitrogen
fertilizers and acid rain, which enhance release of NO2 at the earth's

surface. NO is formed at temperatures above 2000 degrees Centigrade in Q
nuclear explosions and in jet engines.

a oy.

Distributions

oni
3 > Availability Codes |

lAvail endfor
sist | Special

ell | 8



55.

56.

57.

58.

59.

61.

62.

63.

65.

Calabrese, E. J., J. Victor and M. A. Stoddard. "Influence of Dietary Vitamin E on
Susceptibility to Ozone Exposure.” Bull. Env. Contam. Toxicol. 34:417 - 422,
1985.

Goldstein, B. D., M. R. Levine, R. Cuzzi-Spada, R. Cardenas, R. D. Buckley and 9. J.
Balchum. “Para Amino Benzoic Acid as a Protective Agent in Ozone Toxicity.”
24:243 - 247, 1972.

Gong, H., J. F. Bedi and S. M. Horvath. "Inhaled Albuterol Does Not Protect against
Ozone Toxicity in Nonasthmatic Athietes." Arch. Env. Health 43:46 - 53, 1988.

Hackney, J. D. , W. S. Linn, R. D. Buckley, M. P. Jones, L. H. Wightman, S. K. Karuza,
R. L. Blessey and H. J. Hislop. "Vitamin E and Respiratory Effects of Ozone in
Humans.” J. Toxicol. Env. Health 7:383 - 390, 1981.

Holroyde, M. C. and A. A. Norris. "The Effect of Ozone on Reactivity of Upper and
Lower Airways is Guinea Pigs.” Brit. J. Pharmacol. 94:938 - 946, 1988.

. Scheiegle, E. S., W. C. Adams and A. D. Siefkin. “Indomethacin Pretreatment Reduces

QOzone-Induced Pulmonary Function Decrements in Human Subjects." Am.
Rev. Resp. Dis. 136:1350 - 1354, 1987.

Hackney, J. D., W. S. Linn, R. D. Buckley, C. R. Collier and J. G. Mohler. “Respiratory
and Biochemical Adaptations in Men Repeatedly Exposed to Ozone.” In
Environmental Stress, Academic Press, New York, 1978.

Nickula, K. J., D. W. Wilson, D. L. Dungworth and C. G. Plopper. "In Vitro Evidence of
Cellular Adaptation to Ozone Toxicity in the Rat Trachea." Toxicol. Appl.
Pharmacol. 93:394 - 402, 1988.

Kulle, T. J., J. H. Milman, L. R. Sander, H. D. Kerr and W. R. Farrell. “Pulmonazy
Adaptation to Ozone in Subjects with Chronic Bronchitis.” Environ. Res. 34:55
- 63, 1984.

Holizman, M. J., L. M. Fabbri, B. E. Skoogh, P. M. O'Byme, E. H. Walters, H. Aizaa and
J. H. Nadel. "Time Course of Airway Hyprresponsiveness Induced by Ozone in
Dogs." J. Appl. Physiol. : Respirat. Environ Exercise Physiol. 55:1232 - 1236,
1983.

Bromberg, P. A. and M. A. Hazucha. "Is Adaptation te Ozone Protective?" Am. Rev.
Resp. Dis. 1251489 - 490, 1982.

16 US. GOVERNMENT PRINTING OFFICE: 990 - 7-42000679


Several papers deal with the exacerbating effects of exercise on the
pulmonary response to ozone exposure (19-26), all showing the well-
known complement of symptoms consisting of reduced tolerance to exercise
and compromise of pulmonary function at somewhat lower levels than was
previously thought to be effective. Mild respiratory irritation was found in
the whole group of heavily exercising healthy young men at 0.16 ppmv
ozone; two men showed subjective responses at 0.14 ppmv and one of those
two showed responses at 0.12 ppmv. Objective spirometric data, however,
failed to show effects (24). Another study (25) showed on six groups of
exercising healthy young men that forced expiratory spirometric variables
were adversely affected by 0.12, 0.18 and 0.24 ppmv. Coughing was
observed in all subjects. In yet another study (26) ten trained athletes, in
conditions simulating competitive exercise, were exposed to 0.12, 0.18 and
0.24 ppmv ozone and to filtered air. One, five, and seven subjects,
respectively, did not complete the exercise protocol, whereas all completed
the protocol in filtered air. These studies led to the concept of the "effective
dose"- the product of ozone concentration, time of exposure and minute
ventilatory volume (Ve) {19). These authors emphasize, as was pointed oui
in 1980 (4), that ozone concentration is the predominant factor in
determining the effective dose.

These latter studies indicate that cezone can cause symptoms and
objectively-determined compromise of pulmonary function in heavily
exercising people at levels well below current Environmental Protection
Agency and FAA standards. More stringent urban air ozone standards have
been urged (27).

Four studies were found that examined the effects of ozone on disease
processes (28-31). In human beings, the general finding was that czone
(0.25 ppm) had no significant effect on exercising people with chronic
obstructive pulmonary disease (28) or in selected patients with heart
disease exposed to 0.20 to 0.30 ppmv (29). In mice infected with influenza
and exposed to 1.0 ppmv ozone for !, 2, 3, 4, or 5 days for 3 h/d, there was
a twofold increase in mortality and a 3 d decrease in survival time after the
second day of exposure (30). Van Louveren, et al. (31) exposed rats
infected with Listeria monocytogenes to 9.25 or 2.0 ppmv ozone for one
week. Ozone was found to suppress the capacity of lung macrophages to
ingest and destroy Listeria, further, ozone had a suppressive effect on the
development of cellular immune responses to Listeria, i.e., T-cell-dependent
immunity.



DOT/PAA/AM-89/13

Office of Aviation Medicine
Washington, D.C. 20591

AD-A233 156

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Final Report

Airliner Cabin (

Ozone:

An Updated Review
CE. Melton, Ph.D.

December 1989 br

DTIC
Se

This document is available to the public
through the National Technical Information
Service, Springfield, Virginia 22161.

US.Department of Transportation
Federal Aviation Administration

91 4 04 039


Type II pneumocytes to ozone in vitro caused an increase in the
mitochondrial component of superoxide dismutase; electron microscopy,
however, failed to reveal that cell membranes were damaged (46). Ozone in
vitro increased the ability of human lung alveolar macrophages to secrete
chemotactic agents that stimulate the migration of peripheral blood
neutrophils and monocytes, implying that these macrophages play a role in
recruiting of leucocytes in response to lung injury by ozone (47).

Ceil membrane tryptophane is responsible for cell membrane native
fluorescence. Ozone levels in vitro that cause a 50 to 75 p-rcent loss of
fluorescence tesult in about a 10 percent decline in tryptophane, suggesting
that ozone has a predilection for this hydrophilic amino acid. The authors
claim that the red cell membrane is a primary site of ozone toxicity, as
demonstrated by lipid peroxidation, increased osmotic fragility and loss of
cell membrane acetylcholine esterase (48). It is suggested that ozone
contributes to the development of emphysema by inactivation of alpha 1-
proteinase inhibitor (49). Airway epithelium of the dog apparently releases
a factor that promotes relaxation of trachealis smooth muscle. Hyper-
responsiveness to ozone ef dog airway smooth muscle was not accompanied
by decreased quantities of this factor (50). It was shown that exposing rats
lungs to 2.0 ppmv ozone in vitre led to an increased release of short chain
fatty acids, indicating that ozone cay ~. destruction of cellular lipids (51).
Several papers indicate that toxic ,eroxidation intermediates caused by
ozone damage adversely affect adjacent cells (39). How far this spreading
toxicity is effective is apparently not known. it was shown that a stream of
ozone-containing air caused peroxidation of arachidonic acid; such
peroxides had biological activity similar to prostaglandin endoperoxides, ir
that they caused contraction of smooth muscle strips and caused platelet
aggregation. The effects were not inhibited by alpha tocopherol (52). It has
been suggested that thyroxine may enhance ozone toxicity, in that
erythrocytes in vitro show increased cation permeability when the
hormone is added during ozone exposure (53).

CONCLUSIONS

The above studies, mainly in vitro, show that ozone causes a broad
spectrum of nonspecific damage to cells and that the damage may be
spread by toxic oxidative intermediate breakdown products. Although
there is some dispute about whether ozone itself destroys cell membranes
by lipid peroxidation or whether such destruction is secondary to
intracellular free radical production, the end result is the same. Release of
metallic ions from intracellular storage sites, peroxidation of Hpids and
proteins, destruction of cytoskeleton and DNA damage are all included in
the repertoire of ozone effects. Yet, in spite of much work showing damage



permeability of the lung was suggested by a 2-fold increase in albumin and
IgG. Fibronectin 6 increased 6.4-fold and Factor WII increased 2.1-fold; both
are coagulation factors. Urokinase plasminogen activator increased by 3.6-
fold. The authors conclude that 2 fairly brief exposure to ozone (0.4 ppmv)
with light exercise results in increases of several factors related to lung
damage.

The damaging effects of ozone are well-known. The mechanism of such
damage is, to scme extent, speculative but undoubtedly involves the
intracellular production of free radicals - defined as any species that
contains one or more unpaired electrons (39). Examples of free radicals are

the superoxide (O-2 ) and hydroxyl (OH-) radicals resulting from hyperoxia
that participate in lung damage and a host of other conditions (40). Ozone is
not a free radical nor does it form a free radical when it breaks down into
biatomic oxygen molecule ard an oxygen singlet; that is, neither ozone nor
Singlet oxygen is a partially reduced oxygen product because these species
are at the same oxidation level as elemental oxygen (41). However, singlet
oxygen is a highly reactive species and can produce free radicals that can
have severe consequences as far as cellular metabolism is concerned. The
supercxide radical is naturally produced when electrons from the electron
transport system react with oxygen. This free radical, however, is quickly
dismuted by enzymically active metalloproteins known as superoxide
dismutases (SOD's) - Cu- , Zn- or Mn-containing enzymes specific to the
purpose: to produce hydrogen peroxide, which is just as quickly broken
down by catalase or peroxidase to water and biatomic oxygen. Because
superoxide itself is a very short-lived species, SOD activity has been
accepted as a reliable indicator of superoxide activity.

Dubick and associates (42) hypothesized that ozone acts as an oxidant
stress that is exacerbated by Cu, Zn or Mn deficiency, which is expressed as
impaired SOD activity; the implication being that ozone, upon breakdown,
yields superoxide as an intermediate product which, in the absence of these
metal ions, persists Iong enough to lead to cellular damage or death.
Calabrese et al. (43) point to methyl oleate ozonide as an aberrant
intermediate oxidative product of lipid metabolism caused by ozone-
produced free radicals in vitro.

Intraceilular free radicals have a variety of disruptive effects including
the destruction of lysosomal membranes, thus liberating destructive
enzymes into the cytosol, disrupting mitochondrial and endoplasmic
reticular membranes, and destroying cytoskeletal tubules (44). In rat lung
Type II cells exposed to ozone in vitro, surfactant production, as indicated
by pkosphatidyicholin syrithesis, was reduced (45). Exposure of human


simultaneous cabin and ambient ozone concentrations in two Boeing 747
aircraft in commercial service. Ambient levels were measured by an
outside probe located near the nose of the aircraft; the cabin probe was
located in the forward compartment on the outside wall of the circular
staircase. The GASP system was completely automated and data were
recorded on magnetic tape every 5 minutes. When the cabin air of the B-
747 SP had not been passed through an activated charcoal filter, the
retention ratio was 82.5 percent, whereas passage of the air through a
charcoal filter resulted in about a ten-fold reduction in the cabin ozone
level.

Rogers (1) has reported the resuits of an on-board ozone monitoring
program on commercial airline flights. On 16 of $8 flights at latitudes
greater than 37.5 degrees north and at flight levels at or above 35,000 feet,
cabin ozone levels and time-weighted averages later established by the
tule were exceeded.

The U. S. Air Force uses the C-9 (DC-9) aircraft for aeromedical transport.
On four flights of less than 4 hours’ duration, cabin ozone levels were
monitored. Only once did the level (0.344 ppmv) exceed allowable amounts
of ozone established by the rule (14).

With regard to “ozone sickness,” there is such a plethora of papers
published in the last few years reconfirming that ozone causes lung and
airway damage, that one is left to wonder why it is necessary to do, or
publish, further work in this area.

Exposure to high levels (unspecified) of ozone in an electric motor
factory was claimed to have caused eye and respiratory tract irritation,
headache, fever, chills, dizziness, nausea, vomiting, general malaise and
weakness, radiographic abnormalities of the lung, reduction of ventilatory
function, and blood gas abnormalities (15). In aluminum arc welders
exposed to more than 1.05 ppmv ozone, Ohmori et al. (16) described
alterations in ventilatory function consisting of reductions in maximum
expiratory flow at 25 percent of vital capacity. Those who had worked four
years or more were more compromised than were workers who had been
in the trade for shorter lengths of time. Rats exposed to 0.95 ppmv ozone, 8
hours per day (h/d) for 90 d, exhibited lung damage consisting of reduced
intermediate bronchiolar diameter (17). Impedance of lungs of rats exposed
to 0.64 ppmv ozone for 7 d reportedly changed toward decreased reactance
at higher frequencies, which was interpreted to mean increased peripheral
resistance of the lung (18).


Airliner Cabin Ozone:
An Updated Review

INTRODUCTION

Prior to 1980, there was a great deal of concern about the adverse
effects of ozone on the health and well-being of crewmembers and
passengers in high altitude jet aircraft. These concerns had their origin in
complaints, primarily from flight attendants, consisting of a constellation of
symptoms including sore throat, cough, substernal pain on exertion,
headache, fatigue and eye irritation. Subsequent investigations by the FAA
and others led to the conclusion that ambient air ozone, compressed into
the cabin air, caused physical discomfort (1). Laboratory investigations
confirmed and extended conclusions already in the literature that sea level
concentrations of ozone below 0.3 parts per million by volume (ppmv) were
innocuous for normal people in that significant effects of such exposures
did not outlast the exposure period (2,3). A later review of the literature
led to the conclusion that a short-term innocuous dose of ozone
(concentration x time of exposure) was also innocuous over the long term
(4). It was further concluded that concentration is more important than is
duration of exposure in determining the toxicity of a dose of ozone.

RESULTS AND DISCUSSION

The Federal Aviation Administration responded to these findings with
rulemaking that required cabin ozone levels during flight above 18,000 feet
mean sea level be maintained at or below 0.25 ppmv (sea level equivalent)
at all times and that the time-weighted average not exceed 0.1 ppmv
during any 3 hour (h) interval (5,6). Aircraft manufacturers and airline
operators responded to the rule with various strategies for mitigating cabin
ozone contamination, among which were the installation of catalytic filters
to destroy ozone in the cabin air delivery system and by flight planning to
avoid known areas of high atmospheric ozone concentration.

Since the final rule was published in 1980, few reports have appeared in
the literature specifically related to airliner cabin ozone contamination.
However, reports abound on the health effects of ozone and on
anthropogenic factors in the depletion of stratospheric ozone. Most of these
reports respond to concerns about urban air pollution from combustion of
hydrocarbon fuels and from fears of excessive solar radiation at the earth's
surface consequent to depletion of the stratospheric ozone layer. The data
in these reports are, nonetheless, somewhat relevant to aitliner cabin ozone
contamination as the effects of ozone on the health of people are the same,
regardless of its source.


REFERENCES

1. Rogers, J. W. “Results of FAA Cabin Ozone Monitoring Pregram in Commercial
Aircraft in 1978 and 1979." FAA-EE-80-10, 1980.

2. Higgins, E. A., M. T. Lategola, J. M. McKenzie, C. E. Melton and J. A. Vaughan. “Effects
of Ozone on Exercising and Sedentary Adult Men and Women Representative
of the Flight Attendant Population.” OAM Report No. FAA-AM-79-20, 1979.

3. Higgins, E. A. M. T. Lategola, C. E. Melton and J. A. Vaughan. "Effects of Ozone (0.3
ppmv, 600 g/cu m) on Sedentary Men Representative of Airline Passengers
and Cockpit Crew members.” OAM Report No. FAA-AM-80-9, 1980.

4. Melton, C. E. "Effects of Long-term Exposure to Low Levels of Ozone: A Review.” OAM
Report No. FAA/AM-80-16, 1980.

5. Federal Aviation Administration Final Rule. "Airplene Cabin Ozone Contamination.“
Federal Register (45 CFR 3880), January 1980.

6. Federal Aviation Administration. "Transport Category Airplane Cabin Ozone
Concentration.” Advisory Circular No. 120 - 38, October 10, 19890.

7. National Research Council, Committee on Life Sciences, Board on Environmental
Studies and, Toxicology, Committee on Airliner Cabin Air Quality. The
Airliner Cabin Environment: Air Quality and Safety. National Academy Press,
Washington, D. C. , 1986.

8, Biswas, A. K. The Ozone Layer. Chapter 6. Published for the United Nations
Environment Programme by Pergamon Press, 1979.

©

. Belmont, A. D. “Cabin Ozone and Tropopause Definition" in "Guidelines for Flight
Planning During Periods of High Ozone Occurrence." Report No. FAA-EQ-78-
03, 1978.

10. Brabets, Robert I. “Ozone Measurement Survey in Commercial Jet Aircraft." FAA
Technical Report ADS-5, 1963.

11. Briehi, D. and P. Perkins. “Ozone Concentration in the Cabin of a Gates Learjet
Measured Simultaneously with Atmospheric Ozone Concentrations." NASA
Technical Paper 1340, 1978.

12. Holdeman, J. D. and G. D. Nastrom. “Ozone Contamination in Aircraft Cabins: Results
from GASP Data and Analyses." NASA Technical Memorandum 81671, 1981.

13. Perkins, P., J. D. Holdeman and G. D. Nastrom. "Simultaneous Cabin and Ambient
Ozone Measurements in Two Sceing 747 Airplanes.” Report No. NASA Ti
79166, Vol. 1; NASA E-96; FAA AEE-79-05-Vol. 1, 1979.

14. Lurker, P. A. and G. A. Swoboda. “Ozone Survey of C-9A.” USAF OHEL TR 82-5, 1982.

12


28. Linn, W. S., D. A. Shamoo, T: G. Venet, C. E. Spier, L. M. Valencia, U. T. Anzar and J. D.
Hackney. "Response to Ozone in Volunteers with Chronic Obstructive
Pulmonary Disease." Arch. Environ. Health 38:278 - 283, 1983.

29. Superko, H. R., W. C. Adams and P. W. Daly. "Effects of Ozone Inhalation During
Exercise in Selected Patients with Heart Disease." Am. J. Med. 77:463 - 479,
1984.

30. Selgrade, M. J. K., J. W. Iling, D. M. Stames, A. G. Stead, M. G. Menache and M A.
Stevens. "Evaluation of Ozone Exposure on Influenza Infection in Mice Using
Several Indicators of Susceptibility.” Fundam. Appl. Tox. 111169 - 180, 1988.

31. van Louveren, H., P. J. H. Rombout, Sj. Sc. Wagenaar, H. c. Walvoort and J. G. Vos.
“Effects of Ozone on the Defense to a Respiratory Listeria Monocptogenes
Infection in the Rat." Toxicol. Appl. Pharm. 94:374 - 393, 1988.

32. Gliner, I. A., S. M. Horvath, R. A. Sorich and J. Hanley. "Psychomotor Performance
During Ozone Exposure: Spectral and Discriminant Function Analysis of EEG.”
Aviat. Space Environ. Med. 51:344 - 351, 1980.

33. Gertner, A., B. Bromberger-Bamea, A. M. Dannenberg, Jr., R. Traystman and H.
Menkes. "Responses of the Lung Periphery to 1.0 ppm Ozone.” J. Appl.
Physiol.: Respirat. Environ. Exercise Physiol. 55:770 - 776, 1983.

34.  Gertner, A., B. Bromberger-Barmea. M. Dannenberg, Jr., R. Traystman and H.
Menkes. "Effects of Ozone on Peripheral Lung Reactivity.” J. Appl. Physiol.:
Respirat. Environ. Exercise Physiol. 55:777 - 784, 1983.

35. Jones, G. L., P. M. O'Byme, M. Pashley, R. Serio, J. Jury, C. G. Lane and E. E. Daniel.
“Airway Smooth Muscle Responsiveness from Dogs with Airway
Hyperresponsiveness after Ozone Inhalation." J. Appl. Physiol.: Respirat.
Environ. Exercise Physiol. 65:57 - 64, 1988.

36. Barry, B. E., R. R. Mercer, F. J. Miller and J. D. Crapo. "Effects of Inhalation of 0.25
ppm Ozone on the Terminal Bronchioles of Juvenile and Adult Rats." Exp.
Lung Res. 14:225 - 245, 1985.

37. Tyler, W. S., N. K. Tyler, J. A. Last, M. A. Gillespie and T. J. Barstow. “Comparison of
Daily and Seasonal Exposure of Young Monkeys to Ozone. " Toxicology 50:131 -
144, 1988.

38. Koren, H. S., R. B. Devlin, D. E. Graham, R. Mann, M. P. McGee, D. H. Horstman, W. J.
Kozumbe, S. Becker, D. E. House, W. F. McDonnell and P. A. Bromberg. “Ozone-
Induced Infiammation in the Lower Airways of Human Subjects." Am. Rev.
Resp. Dis. 139:407 - 415, 1989.

39. Halliwell, B., "Oxidants and Human Disease: Some New Concepts. The FASEB Jour.
115:358 - 364, 1987.

40. Jamieson, D., B. Chance, E. Cadenas and A. Boveris. "The Relation of Free Radical
Production to Hyperoxia." Ann. Rev. Physiol. 48:703 - 719, 1986.

14


‘yy

Technical Report Documentation Page

T. Report No. 2. Government Accession No. 3. Recipient's Catalog No.

DOT/FAA/AM-89/13

&. Title ond Subtitle 5. Report Date

Airliner Cabin Ozone: An Updated Review December 1989
6. Performing Organization Code

8. Performing Organization Report No.

7. Author’s)
C.E. Melton, Ph.D.
9. Perfcrming Orgenization Name ond Address 10. Work Unit No. {TRAIS)

TT. Contract or Grant No.

13. Type of Report and Period Covered

12. Sponsoring Agency Nome end Address.

FAA Office of Aviation Medicine
Federal Aviation Administration
800 Independence Avenue, SW. 14. ‘Sponsoring Agency Code

Washington, D.C. 20591

15. Supplementary Notes

16; Abstract
-The recent literature pertaining to ozone contamination of airliner cabins is
reviewed. Measurements in airliner cabins without filters showed that ozone
levels were about 50 percent of atmospheric ozone. Filters were about 90 percent
effective in destroying ozone.

Ozone (0.12 to 0.14 ppmv) caused mild subjective respiratory irritation in exer-
cising men, but 0.20 to 0.30 ppmv did not have adverse effects on patients with
chronic heart or lung disease. Ozone (1.0 to 2.0 ppmv) decreased survival time
of influenza-infected rats and mice and suppressed the capacity of lung macro-
phages to destroy Listeria. Airway responses to ozone are divided into an early
parasympathetically mediated bronchoconstrictive phase and a later histamine-
mediated congestive phase.

Evidence indicates that intracellular free radicals are responsible for ozone
damage and that the damage may be spread to other cells by toxic intermediate
products: Antioxidants provide some protection to cells in vitro from ozone
but dietary intake of antioxidant vitamins by humans has only a weak effect,
if any.

This review indicates that earlier findings regarding ozone toxicity do not need
to be corrected. Compliance with existing FAA ozone standards appears to provide
adequate protection to aircrews and passengers.

17. Key Words 16. Distribetion Statement

~ Ozone Air quality Document is available to the public
-Air pollutant Atmospheric contamination through the National Technical
Oxidants Aviation environment ~«—| Information Service, Springfield,

Virginia 22161.

19. Security Classif. (of this report) ‘20. Security Classif. (of this page) 21- No. of Pages | 22, Price

Unclassified Unclassified 19

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized


NOTICE

This document is disseminated under the sponsorship of
the U.S. Department of Transportation in the interest of
information exchange. The United States Government
assumes no liability for the contents or use thereof.



to erythrocytes in vitro, there is still no compelling evidence that ozone
affects eXtrapulmonary systems in vivo. It is simply too fragile, or reactiv.,
a molecule to be transported in the blood or even, pr*haps, to reach the
blood in pulmonary vessels.

Regarding ozone-protective measures, it is claimed that cell lipids can be
protected, at least to some extent, from peroxidation by the essential
nutrients alpha tocopherol, ascorbic aci¢ and beta carotene. All of these
vitamins scavenge free radicals and singlet oxygen (54). Vitamin E
supplementation was shown to protect erythrocytes in vitro from ozone-
induced damage (55). Similarly, para-aminobenzoic acid (PABA), para-
aminohippuric acid and anthranillic acid were shown to protect
erythrocytes in vitro from damage by 40 (!) ppmv ozone. PABA-injected
rats were protected in vivo from 15 ppmv ozone (56). Inhalation of
albutero!, a bronchodilating agent, had no protective effect in athletes
exposed to 0.21 ppmv ozone (57). Vitamin E supplementation did not
protect human subjects from the respiratory effects of a 2 h exposure to 0.5
ppmv ozone (58). Exposure of conscious guinea pigs to 3.5 ppmv ozone for
30 min rendered their lower airway, but not their upper airway, more
sensitive to intravenous. histamine administered under anesthesia;
vagotomy had no effect on the response (59). Indomethacin, a
prostaglandin synthetase inhibitor, significantly improved forced vital
capacity and 1 sec forced expiratory volume in exercising healthy human
subjects exposed to ozone. The findings suggest that cyclooxygenase
products of arachidonic acid that play a prominent role in ozone-induced
pulmonary decrements are sensitive to indomethacin inhibition (60).

Agents that are claimed to protect against ozone seem to be either
ineffective or only weakly effective in humans. Dietary content of free
radical scavengers likewise does not seem to have a marked effect on ozone
toxicity in vivo. As pointed out earlier, responses to ozone appear to be
divided into an early bronchoconstrictive phase that is parasympathetically
mediated and a late phase that is histamine mediated. It would probably be
profitable, or at least informative, to explore further the effectiveness of
parasympatholytic agents and antihistamines on airway responses to ozone.

One persistently peculiar aspect of the pulmonary response to ozone is
“adaptation,” i.e., an attenuated response upon repeated or prolonged
exposure to ozone (61). Such adaptation can be demonstrated at the cellular
level in vitro (62) as well as in intact animals and humans (61, 63).
Adaptation in humans appears to last only 4 to 5 d after cessation of ozone
exposure (63). It has been suggested that the pulmonary irritation in
response to ozone is reversible after about a week of exposure to ozone,

10


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18.

19.

20.

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22.

23.

24.

25.

26.

27.

Ng, T. P., T. W. Tsin and J. F. O'Kelly. "An Outbreak of Ilness after Occupational
Exposure to Ozone and Acid Chlorides.” Brit. Jour. Ind, Med. 42:686 - 690, 1985.

Ohmori, K. T. Tazawa, Y. Ikemi, Y. Kobayashi and M. Kitazumi. “Pulmonary
Functions Otserved by Means of Flow-Volume Curve in Welders Exposed to
Ozone.” Sangyo Igaku, 23:394-400, 1981.

Barr, Bradd C., D. M. Hyde, C. G. Plopper and D. L. Dungworth. “Distal Airway
Remodeling in Rats Chronically Exposed to Ozone. " Amer. Rev. Resp. Dis. 137 :
924 - 938, 1988.

Hotlikoff, M. L, A. C. Jackson and J. W. Watson. “Oscillatory Mechanics of the
Respiratory System in Ozone-Exposed Rats." J. Appl. Physiol. : Respirat.
Environ. Exercise Physiol. 56: 182 - 186, 1984.

Adams, W. C., W. M. Savin and A. E. Christo. “Detection of Ozone Toxicity During
Continuous Exercise via the Effective Dose Concept.” J. Appl. Physiol.
Respirat. Environ. Exercise Physiol. 51:415 - 422, 1981.

Adams, W. C. and E. S. Echelegle. "Ozone and High Ventilation Effects on Pulmonary
Function and Endurance Performance.” J. Appl. Physiol. : Respirat. Environ.
Exercise Physiol. 55:805 - 812, 1983.

Folinsbee, L. J., J. H. Bedi and S. M. Horvath. “Pulmonary Function Changes after
One Hour Continuous Heavy Exercise in 0.21 ppm Ozone". J. Appl. Physiol. :
Respirat. Environ. Exercise Physiol. 57:984 - 987, 1984.

Foster, W. M., D. L. Costa and &. G. Langenbeck. “Ozone Exposure Alters
Trachecbronchial Mucociliary Function in Humans." J. Appl. Physiol. :
Respirat. Environ. Exercise Physiol. 63:996 - 1002, 1987.

Gibbons, S. and W. C. Adams. "Combined Effects of Ozone Exposure and Heat on
Exercising Females." J. Appl. Physiol. : Respirat. Environ. Exercise Physiol.
57:450 - 456, 1984.

Linn, W. S., S. L. Avol, D. A. Shamoo, C. E. Spier, L. M. Valencia, T. G. Venet, D. P.
Fischer and J. D. Hackney. "A Dose-Response Study of Healthy, Heavily
Exercising Men Exposed to Ozone at Concentrations Near the Ambient Air
Quality Standard.” Toxicol. Ind. Health 2:99 - 112, 1986.

McDonnell, W. F., D. H. Horstman, M. J. Hazucha, E. Seal, Jr, E. D. Haak, S. A. Salaam
and D. E. House. Pulmonary "Effects of Ozone Exposure During Exercise: Dose-
Response Characteristics.” J. Appi. Physiol.: Respirat. Environ. Exercise
Physiol. 54:1345 - 1252, 1983.

Schelegle, E. E. and W. C. Adams. "Reduced Exercise Time in Competitive Simulations
Consequent to Low-Level Ozone Exposure.“ Med. Sci. Sports Exerc. 18:408 - 414,
1986.

Sun, M. “Tighter Ozone Standards Urged by Scientists.” Science 240:1724 - 1725,
1988.

13