United States Office of Research and EPA/600/8-88/105F 

Environmental Protection Development January 1992 

Agency Washington DC 20460 

N, 

EPA/600/8-88/ 105F 

JANUARY 1992 

SLTMIVIARY OF SELECTED NEW INFORMATION 

ON EFFECTS OF OZONE 

ON HEALTH AND VEGETATION 

Supplement 

to 

Air Quality Criteria for Ozone 

and Other Photochemical Oxidants 

Environmental Criteria and Assessment Office 

Office of Health and Environinental Assessment 

U. S. Environmental Protection Agency 

Office of Research and Development 

Research Triangle Park, NC 27711 

K* Printed on Recycled Paper 
DISCLAIMER 

This document has been reviewed in accordance with U.S. Environmental Protection 

Agency policy and approved for publication. Mention of trade narnes or commercial 

products does not constitute endorsement or recommendation for use. 

ii 
CONTENTS 

Page 

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv 

ABSTRACT ....................................... v 

AUTHORS ........................................ vn 

CONTRIBUTORS AND REVIEWERS . . . . . . . . . . . . . . . . . . . . . . . vii 

1. SUMMARY OF SELECTED NEW INFORMATION ON EFFECTS OF 

OZONE ON HEALTH AND VEGETATION . . . . . . . . . . . . . . . . 1-1 

1.1 INTRODUCTION ............................ 1-1 

REFERENCES ................................... 1-2 

2. EFFECTS OF OZONE ON VEGETATION . . . . . . . . . . . . . . . . . 2-1 

2.1 STUDIES RELEVANT TO SELECTION OF THE 

AVERAGING TIME FOR THE SECONDARY NAAQS 

FOR OZONE ............................... 2-1 

2.2 SUMMARY AND CONCLUSIONS: VEGETATION 

EFFECTS ............ ............... ... 2-9 

2.2.1 Exposure Duration . . . . . . . . . . . . . . . . . . . . . . . 2-9 

2.2.2 Peak Concentrations . . . . . . . . . . . . . . . . . . . . . . 2-10 

2.2.3 Comparison of Exposure Indices . . . . . . . . . . . . . . 2-11 

2.2.4Evaluation of the 7-Hour (or 12-Hour) 

Seasonal Mean . . . . . . . . . . . . . . . . . . . . . . . . . 2-11 

REFERENCES ................................... 2-13 

3. EFFECTS OF OZONE ON HEALTH . . . . . . . . . . . . . . . . . . . . . 3-1 

3.1 HEALTH STUDIES RELEVANT TO SELECTION OF 

THE PRIMARY NAAQS FOR OZONE . . . . . . . . . . . . . . . 3-1 

3.1.1 Human Clinical Studies . . . . . . . . . . . . . . . . . . . . 3-1 

3.1.2 Field and Epidemiological Studies . . . . . . . . . . . . . 3-27 

3.1.3 Laboratory Animal Studies . . . . . . . . . . . . . . . . . . 3-43 

3.1.3.1 Effects of Multihour Exposures . . . . . . . . 3-43 

3.1.3.2 Effects of Multiday Exposures . . . . . . . . . 3-45 

3.1.3.3 Effects of Chronic Exposure to Ozone .... 3-46 

3.1.3.4 Animal-to-Human Extrapolation . . . . . . . . 3-52 

3.2 SUMMARY AND CONCLUSIONS: HEALTH EFFECTS 

DATA.................................... 3-56 

3.2.1 Exposure Dynamics for Short-Term Ozone Exposure 

Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-57 

3.2.2 Evaluation of Differential Susceptability of 

Potential Special Risk Groups . . . . . . . . . . . . . . . . 3-61 

3.2.3 Ozone Impacts on Lung Structure/Chronic Disease 

Processes ............................ 3-62 

3.2.4 Ozone Dosimetry Aspects . . . . . . . . . . . . . . 3-64 

REFERENCES ................................... 3-65 

iii 
LIST OF TABLES 

u _ _ er Pa~e 

3-1 Controlled Human Exposure Laboratory Studies Relevant to 

Review of the 1-Hour NAAQS for Ozone . . . . . . . . . . . . . . 3-3 

3-2 Key Human Studies Demonstrating Lung Function 

Decrements Near the Current 1 Hour NAAQS for Ozone ..... 3-10 

3-3 Field and Epidemiologic Studies on Effects of Ozone ....... 3-28 

3-4 Experimental Animal Studies on the Relative Influence 

of Ozone Concentration and Duration of Exposure ......... 3-44 

3 5 Chronic Ozone Effects in Experimental Animals .......... 3-47 

3-6 Studies Relevant to Potential Animal-to-Human 

Extrapolations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-53 

1V 
ABSTRACT 

Since completion of the 1986 air quality criteria document for ozone, additional 

information has become available that warrants consideration by the U.S. Environmental 

Protection Agency (U.S. EPA) in its review of the National Ambient Air Quality Standards 

(NAAQS) for ozone. This summary reviews and evaluates selected literature published from 

1986 through early 1989 on the vegetation and health effects resulting from exposure to 

ozone. Emphasis has been placed on evaluation of key human health effects literature and 

other data most pertinent to determination by U.S. EPA of the appropriate level and form of 

the primary NAAQS and the appropriate form of the secondary NAAQS. 

v 

AUTHORS 

Dr. Daniel L. Costa, Health Effects Research Laboratory, OHR, ORD, U.S. Environmental 

Protection Agency, Research Triangle Park, North Carolina 27711. 

Dr. Lawrence J. Folinsbee, C. E. Environmental, Inc., Suite 200, 800 Eastowne Drive, 

Chapel Hill, North Carolina 27514. 

Mr. James A. Raub, Environmental Criteria and Assessment Office, MD-52, OHEA, ORD, 

U.S. Environrnental Protection Agency, Research Triangle Park, North Carolina 27711. 

Ms. Beverly Tiiton, Environmental Criteria and Assessment Office, MD-52, OHEA, ORD, 

U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711. 

Dr. David T. Tingey, Environmental Research Laboratory, OEPER, ORD, 

U.S. Environmental Protection Agency, 200 S.W. 35th Street, Corvallis, 

Oregon 97333. 

. 

CONTRIBUTORS AND REVIEWERS 

Dr. Robert S. Chapman, Dr. Timothy R. Gerrity, Dr. Carl G. Hayes, Dr. Donald H. 

Horstman, Dr. Hillel S. Koren, Dr. William F. McDonnell, Dr. Frederick J. Miller, and 

Dr. John H. Overton, Health Effects Research Laboratory, OHR, ORD, U.S. Environmental 

Protection Agency, Research Triangle Park, North Carolina 27711. 

Dr. Lester D. Gra.nt and Dr. Judith A. Graham, Environmental Criteria and Assessment 

Office, OHEA, ORD, U.S. Environmental Protection Agency, Research Triangle Park, 

North Carolina 27711. 

Dr. Milan J. Hazucha, Center for Environmental Medicine and Lung Biology, The University 

of North Carolina, Chapel Hill, North Carolina 27514. 

Dr. William Hogsett, Environmental Research Laboratory, OEPER, ORD, 

U.S. Environmental Protection Agency, 200 S.W. 35th Street, Corvallis, Oregon 97333. 

Dr. Allan Marcus, Battelle-Applied Statistics, 200 Park Drive, P.O. Box 12056, Research 

Triangle Park, North Carolina 27709. 

Dr. James H. Ware, Harvard University, School of Public Health, Department of 

Biostatistics, 677 Huntington Avenue, Boston, Massachusetts 02115. 

vil 

1. SLTMIVIARY OF SELECTED NEW INFORMATION 

ON EFFECTS OF OZONE ON HEALTI-I 

AND VEGETATION 

1.1 INTRODLTCTION 

The U.S. Environmental Protection Agency (U.S. EPA) document, Air Quality Criteria 

, for Ozone and Other Photochemical Oxidants, completed in August 1986 provided 

comprehensive evaluation of the relevant scientific literature on ozone published through mid1986 (U.S. Environmental Protection Agency, 1986). The criteria document was prepared 

by the Office of Research and Development for use as the scientific basis for decision 

making by the Agency regarding retention or revision of primary and secondary National 

Ambient Air Quality Standards (NAAQS) for ozone. 

Since coinpletion of the 1986 document, additional information has become available 

that warrants consideration by the Agency in its review of the NAAQS for ozone. As a 

supplement to the 1986 document, this summary reviews and evaluates published literature 

concerning exposure- and concentration-response relationships observed for vegetation effects 

and for health effects in humans and experimental animals. Emphasis has been placed on 

evahiation of new human health effects literature and other data most directly pertinent or 

useful for determining the appropriate level and form of the primary standard and the . 

appropriate form of the secondary standard. Selected important data on dosimetry and on 

experimental animal studies that elucidate concentration x tilne (duration) exposure-response 

relationships have also been included. As required by the Clean Air Act, an earlier external 

review draft of this Supplement (U.S. Environmental Protection Agency, 1988) was publicly 

peer-reviewed by the Clean Air Scientific Advisory Committee (CASAC) of U.S. EPA's 

Science Advisory Board (McClellan, 1989). 

The publications reviewed and evaluated in this supplement were selected from 

approximately 500 new articles and abstracts on the health effects of ozone and from about 

300 new articles and abstracts on the vegetation effects of ozone that appeared as peerreviewed journal publications Qr as proceedings papers from 1986 through early 1989. Since 

1-1 
the time of review by CASAC, several of the abstracts and articles previously cited in the 

draft supplement as "in press" or "submitted for publication" have been publisl'aed. In such 

cases, the citation has been updated in this final version of the supplement, including several 

revised citations of 1989 (a.nd a few later) publications. 

R.EF'ERENCES 

IVIcClellan, R. O. (1989) [Letter of CASAC closure on the 1988 ozone criteria document supp:lement to 

William K. Reilly, Administrator, U.S. Environmental Protection Agency]. Washington, DC: 

U.S. Environmental Protection Agency, Clean Air Scientific Advisory Conunittee; May 1. 

U.S. Environmental Protection Agency. (1986) Air quality criteria for ozone and other photoclhemical oxidants. 

Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria 

and Assessnient Office; EPA report nos. EPA-600/8-84-0200-ef. Available from: N'7CIS, Springfield, 

VA; PB87-142949. 

U.S. Environmental Protection Agency. (1988) Summary of selected new information on effeci:s of ozone in 

health and vegetation: draft supplement to air quality criteria for ozone and other photochemical 

oxidants. Research Triangle Park, NC: Office of Health and Environmental Assessment, 

Environmental Criteria and Assessment Office; EPA report no. EPA-600/8-88/105A. Available from: 

NTIS, Springfield, VA; PB89-135123. 

1-2 
2. EFFECTS OF OZONE ON VEGETATIOIlT 

2.1 STUDIES RELEVANT TO SELECTION OE THE AVERAGIIiTG 

TINIE F012 THE SECONDARY NAAQS EOla OZONE 

A review by Hogsett et al. (1988) discusses the biological, environmental, and 

exposure-dynamic factors (e.g., concentration, duration, frequency, threshold, respite time) 

that influence the magnitude of the biological responses of plants. These factors contribute to 

observed variability in responses, and thus become considerations in measures of exposure 

that best describe plant response to poliutant exposure. The various types of exposure indices 

that have been used historically to describe pollutant exposure were also evaluated. The 

ultimate goal of investigations of factors influencing plant response is to develop exposure 

indices that account for all of the variation in the exposure-response relationship. However, a 

second and more practical goal is that of developing or specifying indices useful for standard 

setting. An index for a standard should be simple, not site-specific, and as generic as 

possible. 

Musselman et al. (1986) examined the influence of two different patterns of ozone (0 3) 

exposure on beans. The studies were conducted in a greenhouse and the plants were exposed 

to either a simulated ambient or a.uniform 0 3concentration. The simulated ambient 

exposures followed the ambient exposure patterns of Riverside, CA (03 concentration range: 

0.058 to 0.40 ppm; peak exposure duration: 0.5 to 1.5 h; and total exposure duration: 6 h). 

The uniform distribution was selected to match the total dose and peak concentration of the 

simulated arnbient exposure (0 3concentration: 0.30 or 0.40 ppm; exposure duration: 

2.3 h). Exposures occurred weekly, and the plants received one, two, or three exposures 

before being harvested 6 days after their last exposure. Both 0 3exposures induced foliar 

injury and reduced plant growth; and the effects of the two distributions were not statistically 

different. Consequently, if the maximum concentrations and "total doses" are equal; peak 

shape appears not to be an important variable. 

Kohut et al. (1988) examined the effect of peak concentration and exposure frequency 

on the responses of kidney beans to 0 3 . The plants were exposed to one of four 03exposure 

regimes: (1) constant exposure to 0.05 ppm daily; (2) fluctuating exposure to 0:08 ppm on 

2-1 
alternate days (Monday, Wednesday, and' Friday); (3) cluster exposure to 0.08 ppm on three 

consecutive days (Wednesday, Thursday, and Friday); and (4) exposure to 0.12 ppm on two 

consecutive days (Thursday and Fri.day) or charcoal-filtered air. The exposure duration was 

4 h and yielded weekly mean concentrations between 0.05 and 0.06 ppm. The test plants 

were grown in pots and exposed to 0 3in open-top chambers under field conditions. Plants 

were harvested weekly throughout the study. Although there were two replicates of each 

03treatment, the experiment was not replicated in time. In the early harvests„ the plants 

receiving the peak exposures were significantly impaired. By the final harvest (12 weeks), 

however, there were no significant effects of 0 3on any of the plant growth or yield 

parameters. The authors concluded that the plants integrated the impacts, and, consequently, 

that "...the response of the plants was related to the mean rather than the peak concentration 

of exposure." This conclusion is difficult to substantiate with the data, as none of the 

03exposures produced a significant effect at the final harvest. It is therefore iiot possible to 

determine whether the various treatments differentially affected plant response. 

Heagle et al. (1986) studied the responses of soybeans to chronic doses oiF ozone applied 

in two different ways. Plants were grown in the field using standard National Crop Loss 

Assessment Network (NCLAN) methodology except for the way in whiclz the 0 3was 

dispensed. In one set, various constant amounts of 0 3were added to the ambient air for 

7 h/day; for the second set, the 0 3was increased above the ambient air by proportional 

amounts. Although there was a constant addition of 0 3to the ambient air, in the constantaddition treatments, the resultant exposure regime was not "square wave" because the 

03concentxation in the ambient air varied throughout the exposure. The principle effect of 

the constant addition or proportional addition treatments was to create various levels of 

exposures. The 03concentrations were expressed as the 7-h seasonal means. The authors 

concluded that the two different types of exposure regirnes produced identical responses. 

Several trends in the data, however, cast doubt on the validity of this conclusion. The 

authors clearly state that the proportional additions caused the more frequent occurrence of 

elevated concentrations, but their exposure index (the 7-h seasonal mean) failed to 

characterize or reflect this elevated exposure. In fact, the 7-h means for the proportional 

additions were lower than those for the comparable constant-addition treatments. The authors 

also reported that the slope of the "dose-re'sponse curve" for the proportional additions was 

2-2 
greater than for the constant additions. The authors speculated that an extension of the dose 

range might have shown significant results. The failure of the 7-h seasonal mean to 

adequately characterize the higher concentrations is not surprising beca.use a previous paper 

(Cure-et al. , 1986) from the same group states that the 7-h seasonal mean was selected 

specifically because it was less sensitive to variations in 0 3patterns. Consequently, the 

conclusions of the authors must be viewed with skepticism. 

Heagle et al. (1987) also evaluated the influence on tobacco yield of daily 0 3exposure 

duration and fluctuations in concentrations. Plants were grown in the field using standard 

NCLAN methodology except for the 0 3-dispensing protocol. In one set of studies, various 

constant amounts of 03were added to the ambient air for 7 h/day; to the second set, the 

03 was increased above the ambient air by proportional amounts. In addition, the study 

compared the effects of 7- and 12-h exposures on tobacco yield. The 0 3concentrations were 

expressed as the 7- and 12-h seasonal means. Yield was reduced to a greater extent by 12-h 

than by 7-h exposures. The authors concluded that the two different types of 7-h exposure 

regimes (7-h consta.nt and 7-h proportional) produced identical responses. 

Additional analyses of the soybean (Heagle et al., 1986) and tobacco (Heagle et al., 

1987) data sets were carried out by Rawlings et al. (1988) to evaluate various exposure 

indices and the influence of exposure duration on plant response. The results from the 

soybean data and the 12-h studies with tobacco suggested that the peaks should be given 

greater weight. In contrast; the 7-h studies with tobacco suggested that the arithmetic mean 

was sufficient and that the peaks did not require additional weighting. Rawlings et al. 

acknowledged that these results must be viewed with caution, because the differences in 

exposure profiles between the constant and proportional 0 3additions were relatively small, 

thus limiting the power of the experiment for determining the "best" exposure index. This 

same caveat also applies to the conclusions reached by the authors of the soybean (Heagle 

et a1., 1986) and tobacco (Heagle et al., 1987) studies. The analysis of exposure duration 

found that 12-h exposures caused greater effects than 7-h exposures (Rawlings et al., 1988). 

The negative impact of the exposures did not increase linearly with exposure duration (i.e., 

the decrease in yield loss was not directly proportional to the increased length of exposure). 

In a study by Adomait et al. (1987), white beans (Phaseolus vulgaris) were grown in 

field plots throughout southern Onta.rio, Canada. Piants at each location were treated with a 

2-3 
chemical protectant, ethylenediurea. (EDU), to reduce or eliminate the impact of 0 3on yield, 

which was determined as the difference between the yields of EDU and non-EDU treated 

plots at each location. Ozone exposure was expressed as the cumulative 0 3conicentrations 

above a threshold of 0.08 ppm for the month of August. Yield decreased as the cumulative 

03 concentration increased. The addition of temperature and rainfall to the regression 

equation, in an attempt to approximate 0 3flux into the plant, significantly improved the fit 

of the regression equation to the data. To express the experimental results, the authors 

assumed that the elevated 0 3concentrations (peaks) were irnportant and that the. irnpact was 

the cumulative result of multiple exposures. 

Data used in a study by Cure et al. (1986) were generated using sta.ndard open-top 

chamber NCLAN protocols. The study did a three-way comparison of relationships among 

the 7-h seasonal mean, the 1-h seasonal rnean, and the 1-h maximum for the seELson. For two 

of the three comparisons, the 7-h/1-h ratio was essentially consta.nt, suggesting i:hat these two 

variables differed by a consta.nt. For the other comparison, the ratio was less stable. The 

authors concluded, however, that the 7-h and 1=h seasonal means were surrogate,s for each 

other. The ratio of the 1-h maximum to the 7-h seasonal mean was highly unstable, which 

suggests that the maximum was poorly related to the long-term mea.n. The authors selected a 

seasonal mean for two reasons: (1) They assumed that crop yield reductions resulted from an 

accumulation of daily 0 3effects over the growing season; a.nd (2) the seasonal ineans were 

much less sensitive to peak variations in yearly 0 3patterns, especially at concentrations near 

the current ambient levels. 

In a study by McCool et al. (1986), plants grown in a standard soil were exposed to a 

range of 03levels in closed-top exposure chambers and the yields were determined. The 

authors developed yield-loss functions that related decreased crop yield to a curnulative 

exposure index for 12 crops. Ozone exposure was characterized as the cumulative 

concentrations greater than 0.10 ppm. The concentration threshold (0.10 ppm) was chosen 

because it was the California state 03standard. A threshold concentration for 0 3was used 

to avoid giving equal mathematical weight to the numerous low concentrations a lrid to ignore 

the low nighttime background in calculating the exposure. 

In a field study using closed-top exposure chambers, McCool et al. (1987) assessed the 

impact of Ogon four vegetables (turnip, beet, onion, lettuce). The exposure-response 

2-4 
functions were best described as a linear function with increasing exp.osure. Both the sum of 

the concentrations > 0.10 ppm and the 12-h seasonal mean concentration were used in 

developing the exposure-response functions. Neither exposure index was uniformly best. 

A 3-year field study was conducted by Smith et al. (1987) in which the effects of 0 3on 

foliar injury and yield were assessed using the chemical protecta.nt EDU. Ozone exposure 

was characterized as the 7-h seasonal mean and as the cumulative exposure (using various 

concentration thresholds). The EDU treatment did not significantly enhance crop yieid. 

Yield and foliar injury, respectively, were similar among cultivars and over years. Although 

the ambient 03 exposures between 1983 and 1984 were substantiaily different, as indicated by 

the various cumulative statistics, this difference was not reflected in the 7-h seasonal mean. 

These data are a.nother example of the lack of sensitivity of the mean to temporal variations 

in 03exposures: 

Open-top chambers were used by Wang et al. (1986a) in a field study to exarnine the 

effects of ambient 03on the growth and foliar injury of three tree species. Ozone was 

characterized as the number of daily occurrences above 0.08 and 0.12 ppm. The authors 

concluded that 0 3 significantly impaired the growth of hybrid poplar in the absence of visible 

foliar injury. There were 20 days when 0 3exceeded 0.08 ppm and 1 day when the 

concentration exceeded 0.12 ppm. In a 3-year study with quaking aspen, Wang et al. 

(1986b) found that plant growth was reduced 12 to 24 %. In only one of the years was the 

current National Ambient Air Quality Sta.ndard for 0 3exceeded. The observations that 

growth reductions can occur in the absence of the ambient 0 3concentration exceeding the 

level of the current standard are consistent with the recent analysis of Lee et al. (1989), 

which forecast significant effects oir crop yield when the standard was not exceeded. 

Only a limited number of studies have been conducted with the specific objective of 

developing or evaluating various exposure indices; several studies have reanalyzed existing 

exposure-response data to evaluate a range of exposure indices. The results of these 

retrospective analyses have provided useful concepts and their conclusions are in general 

agreement. Because the experiments analyzed were not specifically designed to evaluate 

various indices; the differences among the actual exposure treatments (frequency of 

03 occurrences) may be relatively small. Consequently, the power of these studies is less 

than desirable. 

2-5 
Reanalysis of several NCLAN data sets (soybean a.nd wheat from Argonne, IL; cotton 

from Shafter, CA; and alfalfa from Corvallis, OR) was performed by Lee et al. (1987) using 

various mean and cumulative peak-weighted exposure indices (e.g., concentrati<in threshold 

and funetional pealc weighting). Exposure indices that included all the data (24 h) performed 

better than those that used only 7 h of data. The 7-h seasonal mean was never "best" and 

was near optimal in only 5 of 14 cases. From a modeling standpoint, the exposure indices 

that emphasized peaks performed better than those that gave equal weighting to al1 

eoncentrations; indices that accumulated the exposures performed better than those that 

averaged the exposures. 

In a more extensive retrospective a.nalysis of NCLAN data, Lee et al. (1988) fit 

24 common and 589 general phenologically weighted, cumulative-impact (GPW(CI) exposure 

inclices to the response data from seven crop studies (2 years of data for each). The "best" 

exposure indices were those that displayed the smallest residual sums of square error when 

the yield response data were regressed on the various 0 3exposure indices using the BoxTidwell model. The "best" exposure index was a GPWCI with sigmoid weighting on 

eoncentration and a gamma weighting function as a surrogate for changes in plaait sensitivity 

over time. Cumulative indices (with concentration thresholds) performed as well as the 

GPWCIs, whereas mean indices did not perform as well. The general conclusions of the 

autliors were, "While no single index was deemed "best" in relating ozone exposure to plant 

response, the top-performing indices were those indices that (1) cumulated the hourly ozone 

concentrataons over time, (2) used a sigmoid weighting scheme which emphasizes 

concentrations of 0.06 ppm and higher, and (3) phenologically weighted the exposure such 

that the greatest weight occurs during the plant growth stage. These findings illustrate the 

importance of the duration of exposure, the importa.nce of repeated peaks, and tYte time of 

increased sensitivity in assessing the impact of ozone on plant growth. " Although peak 

concentrations should be given greater weight, the authors suggested that lower concentrations 

sltould also be included but given lesser weight in the calculation of a.n exposure index. 

The paper by Tingey et al. (1989) is essentially a condensation of the paper by Lee 

et al. (1988) and therefore the conclusions are basically the same. However, the: paper does 

show the iinportance of exposure duration in influencing the magnitude of plant response and 

the limitation of the seasonal mean to specifically incorporate varying exposure d:urations. 

2-6 
For example, the mean cannot distinguish among exposures to the same average 

concentrations over different durations (e.g., for 10, 50, or 100 days). 

Wheat and soybea.n data sets (Kohut et al., 1987, 1986) collected using standard 

NCLAN protocols at Ithaca, NY, were reanalyzed by Lefohn et al. (1988a) to compare 

exposure indices. The authors used the 7-h mean a.nd cumulative statistics with thresholds, 

or peak weighting. The data were fit with both linear and Weibull response models. No one 

exposure statistic was best for all data sets or response models. The linear model showed no 

strong tendency to fit any exposure index; however, a peak-weighted statistic and the number 

of occurrences > 0.08 ppm or the sum of the concentrations > 0.08 ppm had a higher 

R2than the 7-h seasonal statistic. When the Weibull model was used, the cumulative 

statistics performed better than the seasonal means. The authors also concluded that a 

sigmoid peak-weighted scheme was better than a threshold approach because it included the 

effects from the concentrations below the selected threshold concentration but gave thern less 

weight. 

The paper by Lefohn et al. (1988a) has engendered discussion in the literature about the 

interpretation of the data (Runeckles, 1988; Parry and Day, 1988). Both groups of 

respondents thought that the paper contained insufficient data and evidence to support the 

conclusion that peak-weight exposure indices should be used in developing exposure-response 

functions. However, Runeckles tempered his criticism with the observation that peakweighted 'indices perforined at least as well as inean indices. Also, the respondents criticized 

the cornpilation of the 2 years of wheat data into a single model when the exposure durations 

were markedly different. In response, Lefohn et al. (1988b) stated that the wheat data 

support the need to include a cumulative component in an exposure index. They concluded 

that, "The cumulative index is more relevant to use in the standard-setting process than 

seasonal means, which ignore the length of the exposure period." 

Musselman et al. (1988) conducted a retrospective analysis of crop loss data originally 

collected by Oshima et al. (1976) (see U.S. Envirorimental Protection Agency, 1986). The 

analysis was based on data for five crops, but those data were not replicated in time. The 

plants were grown in pots in standardized soil and were provided with adequate water and 

nutrients. The plants were placed at 9 to 12 sites along an ainbient 0 3concentration gradient 

in the Los Angeles Basin. The crop loss data were originally summarized by Oshima et al. 

2-7 
(1976) on the basis of the cumulated concentration above 0.10 ppm for the growing season. 

In this study, the authors tested (1) various peak indices, (2) daily mean indices, and 

(3) indices based on subsets of a 24-h day: No single exposure index was "best" for the five 

crops. Ozone indices utilizing a concentration threshold level performed well for most 

crops, but the optimum threshold level varied with the particular index calculated. Some of 

the "better" indices were (1) seasonal mean of concentrations above 0.09, 0.12, or 0.14 ppm; 

(2) mean of all daily peak concentrations; (3) sum of the daily peaks squared above a 

concentration of 0.15 ppm; and (4) total number of seasonal peaks above 0.12 pprn. The 

7- or 12-h seasonal means were not among the better-performing indices. 

Lazsen et al. (1988) evaluated 14 0 3exposure indices for their ability to predict crop 

yield loss. The second highest daily maximum concentration and 13 other indices, including 

the effective mean 0 3concentration and the summer daytime average (M7), we:re calculated 

for 80 "agricultural" National Aerometric Data Bank sites and for multiple years, for a total 

of 320 site-years. In contrast to other retrospective analyses, separate exposure.-response 

functions were not derived from biological data for each exposure index. Larsen et al.. 

(1988) used ambient air monitoring data to derive correlations between the effective mean 

and other air quality indices. These correlations (based only on ambient air monitoring data) 

were used to express the plant response data in terms of the different indices (i. e. , the 

lognorinal model that expressed crop reduction as a function of the effective mean 

concentration [Larsen and Heck, 1984] was used to generate crop loss estimates for the 

320 site-years of ambient data). Because there was no ,biological variation in the data, 

correlations between the exposure indices and estimated crop reductions were, in fact, 

measures of association between the (transformed) effective mean and the other indices. 

Consequently, no evidence that the mean indices were better correlated with plant response 

than other indices can be inferred from the analysis of Larsen et al. (1988). 

Larsen et al. (1983) developed an exposure-response model that relates 0 3impact on 

plants to a cumulative index that they denoted as the total impact. A 75-day exposure for 

7 h/day was originally assumed for calculating the estimated crop reduction for soybean (this 

may not be representative of the phenological life span of soybean). In the original analysis, 

the effective mean was not calculated from the hourly 0 3concentrations for the NCLAN 

studies but was estimated by multiplying M7 by 1.15 for charcoal-filtered and nonfiltered 

: 
exposures (and supplementing the nonfiltered exposures with the constant additions for other 

exposures). Further, treatment means rather than chamber means were used in estimating the 

lognormal rnodel. Consequently, this lognormal model is inaccurate and needs to be 

estimated more precisely for use in the selection of exposure indices for use as a 03standard. 

The adequacy of the lognormal model using other exposure indices must also be determined. 

Reich and Amundson (1985) have reviewed a series of field and controlled-environment 

studies to assess the impact of 0 3on photosynthesis. The authors stated, "...it may be 

inappropriate as well as difficult to compare directly the response of the species on the basis 

of a mean 03exposure concentration. However, when the responses are compared on the 

basis of a unit dose of 0 3 , the results are more easily interpreted. " A unit dose of 0 3as 

defined by the authors means cumulative exposure (i.e., total parts per million). The 

03-induced decrease in growth was directly related to reduced photosynthesis, which was 

decreased by the cumulative 0 3exposure. 

2.2 SUMMARY AND CONCLUSIONS: VEGETATION EFFECTS 

Recent literature concerning the appropriate averaging time for an exposure index for 

03effects on vegetation was evaluated in relation to (1) the role of dxposure duration, (2) the 

role of peak 03concentrations, (3) comparison of exposure indices, and (4) evaluation of the 

7=h seasonal mean. 

2.2.1 Exposure Duration 

Increasing the duration in the exposure index from a 7-h seasonal mean to a 12-h 

seasonal mean caused a greater decrease in yield. A comparison of 7- and 24-h exposure 

indices showed that 24-h indices provided an even better statistical fit to the exposureresponse data. Although plant effects increased with exposure duration, the study of 

Rawlings et al. (1988) showed that the increase in plant response was not proportional to the 

increase in exposure duration. 

All the recent studies that used impaired plant growth or yield as an adverse effect 

specifically selected exposure indices that might reflect the cumulative impact of effects 

throughout the growing season. For example, Cure et al. (1986) stated that crop yield 

2-9 
reductions result from an accumulation of daily 0 3effects over the growing se:ason. Reich 

and Amundson (1985) stated that the 0 3-induced decrease in growth was directly related to 

reduced photosynthesis, which was impaired by the cumulative 0 3dose. These data can be 

interpreted to mean that growth and yield are reduced by repeated 0 3episodes, because that 

is how 03occurred in the.studies and how it occurs in nature. 

These studies support the conclusion that a cumulative 0 3exposure index is needed that 

reflects the total exposure that the plant experiences. This conclusion is consistent with the 

1986 U.S. EPA criteria document (U.S. Environmental Protection Agency, 1986), which 

states, "When plant yield is considered, the ultirnate impact of an air pollutant on yield 

depends on the integrated irripact of the pollutant exposures during the growth ~of the plant. " 

By inference or deduction, then, a mean of unspecified time (days or months) is 

iziappropriate because the lack of specification of "time" results in a variable duration of , 

03accumulation. 

2.2.2 Peak Concentrations 

IVlost of the recent studies, except for papers reporting results of the NCLAN program, 

selected exposure indices that cumulated the exposure and preferentially weighted the peaks. 

Three main peak-weighting approaches have been used: (1) a concentration threshold 

approach, in which the concentrations above the selected threshold are sumrneci or in which 

the number of days or hours above the concentration threshold are summed; (2) an allometric 

or exponential weighting, in which all concentrations are raised to a specific exponential 

power; and (3) a sigmoid weighting, in which all concentrations are weighted with a 

multiplicative weighting factor (which depends on concentration). 

The threshold weighting approach assumes that only the concentrations above the 

selected concentration threshold are biologically active. Recent studies have sh.own that the 

concentrations below the selected concentration threshold or cutoff may also ha.ve biological 

iniportanee. It is also likely that the appropriate concentration threshold differs between 

species, with environmental conditions, and with endpoint measured. 

Functional weighting approaches using either an allometric or sigmoid we.ighting are 

preferred to the concentration threshold approach. These approaches do not censor 

concentrations, but rather give weight, although not equal, to all concentrations in eliciting a 

2-10 
biological response. Specific comparisons of the functional weighting to the threshold 

approaches showed that they yielded better statistical fits to the data. Also, the sigmoid 

weighting functions appeared to perform better than the allometric weighting approach. 

The conclusions found in recent literature regarding the importance of cumulative peak 

concentrations in causing vegetation responses are consistent with the data and conclusions 

presented in the 1986 criteri.a document (U.S. Environmental Protection Agency, 1986). 

2.2.3 Comparison of Exposure Indices 

There have been several studies (Lee et al., 1987, 1988, 1989; Lefohn et al., 1988a; 

1VIusselman et al., 1988) conducted that were retrospective analyses of existing plant-response 

data sets. These authors evaluated the relative efficacy of existing and proposed exposure 

indices, using a large number of crop data sets. The exposure indices included various means 

and cumulative statistics using both threshold and functional concentration weighting. The 

authors concluded that there was no single exposure index that was best for all crop species 

or for all data sets. These studies are all in agreemeint, however, that (1) mean indices are 

not among the best indices and (2) the preferred (yielded best statistical fit to the data) 

exposure indices curnulated the exposure impact over the growing season and preferentially 

weighted the peak concentrations. 

2.2.4 Evaluation of the 7-Hour (or 12-Hour) Seasonal Mean 

The 7-h seasonal mean is the most commonly used exposure index in the literature 

reviewed in the 1986 U.S. EPA criteria document (U.S. Environmental Protection Agency, 

1986), and it continues to be used by investigators. Mathematically, the mean contains all 

hourly concentrations making up the exposure period and treats all concentrations equally, 

thus implying that (1) all concentrations of 03(across the range of concentrations to which 

plants are exposed in a growing season) are equally effective in causing a response, and 

(2) the contributions of the peak concentrations to the response are minimal. The mean treats 

low-level, long-term exposures the same as high-concentration, short-term exposures; a 

scenario that the literature does not support (e.g., the 1986 U.S. EPA criteria document). An 

infinite number of hourly distributions, from those containing many peaks to those containing 

none, can yield the same 7-h seasonal mean. Cure et al. (1986) reported that mean 

2-11 
characteriza.tions of 0 3exposure were much less sensitive than the daily 1-h maximum to 

variations in yearly 03patterns. Also, Reich and Amundson (1985) stated, "...it may be 

inappropriate as well as difficult to compare directly the response of species on the basis of a 

mean 03exposure concentration. However, when the responses are compared on the basis of 

a unit dose of 03 , the results are more easily interpreted. " 

The use of a mean exposure index for characterizing exposures implies cex -tain 

assumptions. 

1. A. seasonal mean assumes that crop yield reductions result from the 

accumulation of daily 0 3effects over the growing season (Cure et al. , 

1986). 

2. A mean assumes that the distribution of hourly 0 3concentrations (over the 

averaging time) are not highly skewed and that the distribution is uniinodal. 

In the ambient, the 03concentration distributions are frequently skewed 

toward the higher concentrations. 

3. The mean weights all concentrations within the selected averaging tirne 

equally. 

4. The mean does not specifically include an exposure duration compone:nt; it 

camiot distinguish between two exposures to the same concentration but of 

different durations (e.g., 50 or 100 days). 

5. The mean assumes that the selected time interval, over which the 

concentrations are averaged, is the period of highest hourly occurrences of 

0

3or any other pollutant being examined. 

6. The mean index assumes that peak events do not need to be given spe.cial 

consideration. This is not consistent with results showing that short-terin 

peak concentrations are important in determining vegetation response (see, 

e.g., the 1986 U.S EPA criteria document). 

The correlation between the 7-h seasonal mean (M7) and the second-highest daily 

maximum 1-h concentrations (i. e. , HDM2, the current 0 3standard) was low (r = 0.54) due 

to the insensitivity of peak concentrations in the M7 calculation (Lee et al., 1989). A wide 

range of temporal distributions with HDM2 between 0.06 and 0.24 ppm was found at sites 

with M7 values between 0.036 and 0.048 pprn. Temporal distributions of ambient 0 3data at 

83 nonurban sites showed large spatiai differences across these sites, with the HDM2 ranging 

2-12 
from 0.06 to 0.24 ppm. In contrast, the 7-h seasonal mean (M7 calculated from May to 

September) across the 83 sites showed small differences (i.e., 90% of the sites had M7 values 

between 0.03 a.nd 0.06 ppm). 

REFERENCES 

Adomait, E. J.; Ensing, J.; Hofstra, G. (1987) A dose-response function for the impact of 0 3on Ontario-grown 

white bean and an estimate of economic loss. Can. J. Plant Sci. 67: 131-136. 

Cure, W. W.; Sanders, J. S.; Heagle, A. S. (1986) Crop yield response predicted with different 

characterizations of the same ozone treatments. J. Environ. Qual. 15: .251-254: 

Heagle, A. S.; Lesser, V. M.; Rawlings, J. O.; Heck, W. W.; Philbeck, R. B. (1986) Response of soybeans to 

chronic doses of ozone applied as constant or proportional additions to ambient air. Phytopathology 

76: 51-56. ` 

Heagle, A. S.; Heck, W. W.; Lesser, V. M.; Rawlings, J. O. (1987) Effects°of daily ozone exposure duration 

and concentration fluctuation on yield of tobacco. Phytopathology 77: 856-862. 

Hogsett, W. E.; Tingey, D. T.; Lee, E. H. (1988) Ozone exposure indices: concepts for development and 

evaluation of their use. In: Heck, W. W.; Taylor, O. C.; Tingey, D. T., eds. Assessmeiit of crop loss 

from air pollutants: proceedings of an international conference; October 1987; Raleigh, NC. New 

York, NY: Elsevier Applied Science; pp. 107-138. 

Kohut, R. J.; Amundson, R. G.; Laurence, J. A. (1986) Evaluation of growth and yield of soybean exposed to 

ozone in the field. Envi'ron. Pollut. Ser. A 41: 219-234. 

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 wheat. Phytopathology 77: 71-74. 

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. Pollut. 53: 79-88. 

Larsen, R. I.; Heck, W. W. (1984) An air quality data analysis system for interrelating effects, standards, and 

needed source reductions: part S. an effective mean 0 3crop reduction mathematical model. J. Air 

Pollut. Control. Assoc. 34: 1023-1034. 

Larsen, R. I.; Heagle, A. S.; Heck, W. W. (1983) An air quality data analysis system for interrelating effects, 

standards, and needed source reductions: part 7. an 0 3SOzleaf injury mathematical model. J. Air 

Pollut. Control Assoc. 33: 198-207. 

Larsen, R. I.; McCurdy, T. R.; Johnson, P. M.; Heck, W. W. (1988) An air quality data analysis system for 

interrelating effects, standards, and needed source reductions: part 10. potential ambient 0 3standards 

to limit soybean crop reduction. JAPCA 38: 1497-1503. 

Lee, E. H.; Tingey, D. T.; Hogsett, W. E. (1987) Selection of the best exposure-response model using various 

7-hour ozone exposure statistics. Research Triangle Park, NC: U.S. Environmental Protection Agency, 

Office of Air Quality Pianning and Standards. 

2-13 
Lee, E. H.; Tingey, D. T.; Hogsett, W. E. (1988) 'Evaluation of ozone exposure indices in exposure-response 

modeling. Environ. Pollut. 53: 43-62. 

Lee, E. H.; Tingey, D. T.; Hogsett, W. E. (1989) Interrelation of experimental exposure and a:mbient air 

quality data for comparison of ozone exposure indices and estimating agricultural losses. Corvallis, 

OR: U.S. Environmental Protection Agency, Environmental Research Laboratoiy; EPYL report no. 

EPA-600/3-89-047. Available from: NTIS, Springfield, VA; PB89-195036. 

Lefohn, A. S.; Laurence, J. A.; Kohut, R. J. (1988a) A comparison of indices that describe the relationship 

between exposure to ozone and reduction in the yield of agricultural crops. Atmos. Environ. 

22: 1229-1240. 

Lefohn, A. S.; Laurence, J. A.; Kohut, R. J. (1988b) Authors' reply [A response to comments by Runeckles, 

1988b]. Atmos. Bnviron. 22: 1242-1243. 

IvIcC'ool, P. M.; Musselman, R. C.; Teso, R. R.; Oshima, R. J. (1986) Dete rmining crop yield losses from air 

pollutants. Calif. Agric. 40(July-August): 9-10. 

McCool, P. M.; Musselman, R. C.; Teso, R. R. (1987) Air pollutant yield-loss assessment for :Four vegetable 

crops. Agric. Ecosyst. Environ. 20: 11-21. 

Musselman, R. C.; Huerta, A. J.; McCool, P. M.; Oshima, R. J. (1986) Response of beans to simulated 

ambient and uniform ozone distributions with equal peak concentration. J. Am. Soc. Hortic. Sci. 

111: 470-473. 

Musselman, R. C.; McCool, P. M.; Younglove, T. (1988) Selecting ozone exposure statistics for determining 

crop yield loss from air pollutants. Environ. Pollut. 53: 63-78. 

Oshima, R. J.; Poe, M. P.; Braegelmann, P. K.; Baldwin, D. W.; Van Way, V. (1976) Ozone dosage-crop 

loss function for alfalfa: a standardized niethod for assessing crop losses from air pollutants. J. Air 

Pollut. Control Assoc. 26: 861-865. 

Parry, M. A. J.; Day, W. (1988) A comparison of indices that describe the relationship between exposure to 

ozone and the reduction in the yield of agricultural crops [Conunents on article by Lefohn et al., 

1988]. Atmos. Environ. 22: 2057-2058. 

Rawlings, J. O.; Lesser, V. M.; Heagle, A. S.; Heck, W. W. (1988) Alternative ozone dose metrics to 

characterize ozone impact on crop yield loss. J. Environ. Qual. 17: 285-291. 

Reich, P. B.; Amundson, R. G. (1985) Ambient levels of ozone reduce net photosynthesis in tree and crop 

species. Science (Washington, DC) 230: 566-570. 

Runeckles, V. C. (1988) A comparison of indices that describe the relationship between exposure to ozone and 

reduction in the yield of agricultural crops [Comments on article by Lefohn et al., 1988]. Atmos. 

Environ. 22: 1241-1242. 

Snuth, G.; Greenhalgh, B.; Brennan, E.; Justin, J. (1987) Soybean yield in New Jersey relative ito ozone 

pollution and antioxidant application. Plant Dis. 71: 121-125. 

2-14 
Tingey, D. T.; Hogsett, W. E.; Lee, E. H. (1989) Analysis of crop loss for alternative ozone exposure indices. 

In: Schneider, T.; Lee, S. D.; Wolters, G. J. R.; Grant, L. D., eds. Atmospheric ozone research and 

its policy implications: proceedings of the 3rd US-Dutch international symposium; May 1988; 

Nijmegen, The Netherlands. Amsterdam, The Netherlands: Elsevier Science Publishers; pp. 219-227. 

(Studies in environmental science 35). 

U.S. Environmental Protection Agency. (1986) Air quality criteria for ozone and other photochemical oxidants. 

Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria 

and Assessment Office; EPA report nos. EPA-600/8=84-0200-ef. Available from: NTIS, Springfield, 

VA; PB87-142949. 

Wang, D.; Bo +-mann , F. H.; Karnosky, D. F. (1986a) Regional tree ~rowth reductions due to ambient ozone: 

evidence from field experiments. Environ. Sci. Technol. 20: 1122-1125: 

Wang, D.; Karnosky, D. F.; Bormann, F. H. (1986b) Effects of atnbient ozone on the productivity of Populus 

tremuloides Michx. grown under field conditions. Can. J. Ror. Res. 16: 47-55. 

2-15 

3. EFFECTS OF OZONE ON HEALTH 

3.1 HEALTH STUDIES RELEYANT TO SELECTION OF THE 

PRIMARY NAAQS FOR OZONE 

3.1.1 Human Clinical Studies 

The strongest and most quantifiable concentration-response data on the acute health 

effects of ozone (03) are provided by the controlled human exposure studies, in which 

significant decrements in pulmonary function have been reported (U. S. Environmental 

Protection Agency, 1986). In most of these studies, the greatest atterition has been focused 

on decrements in forced expiratory volume in 1 s(FEV 1) because this measure of lung 

function represents a summation of changes in both lung volume and resistance. At the 

lower 03concentrations of interest for standard-setting (<0.12 pprn), however, the observed 

decrements in FEV1primarily reflect decrements in forced vital capacity (FVC), with little 

or no contribution from changes in airway resistance. These changes in FEV 1are caused by 

a reduced inspiratory capacity that most likely results froin sensitization or stimulation of 

airway irritant receptors. 

Scientific evidence presented in the 1986 U.S. EPA criteria document (U.S. 

Environmental Protection Agency, 1986) established that pulmonary function decrements are 

generally observed in healthy adults after 1 to 3 h of exposure as a function of the level of 

exercise performed and the 0 3concentration inhaled during the exposure. Decrements in 

lung function have been reported to occur in some groups of healthy adults at the current 

level of the standard (0.12 ppm) or somewhat higher. Also, pulmonary function decrements 

have been observed in children and adolescents at concentrations of 0.12 ppm and 0.14 ppm, 

respectively, with heavy exercise. At the lower 0 3concentrations in the range 0.12 to 

0.16 ppm, the average group mean changes in lung function are generally small (<_6%), and 

the medical significance of these changes is a matter of controversy. Some individua.ls, 

however, are intrinsically more responsive to 03than others and exhibit noticeably largerthan-average pulinonary function decrements than the rest of the group. Such larger 

(> 10%) decrements in lung function may be of some medical significance to the affected 

individuals. 

3-1 
More recent controlled hu.man exposure studies appearing after the completion of the 

1986 criteria document have further confirmed and extended the above types of fmdings, as 

well as denionstrating some additional new types of effects. The most pertinenr of these 

newer studies are summarized in Table 3-1. The newer studies noted in Table 3-1 add most 

extensively to our knowledge concerni.ng pulrnonary function decrements associated with 

acute 03exposures near the current 1-h NAAQS for 0 3 . The newer pulmonary function 

decrement findings are summarized in Table 3-2 in relation to the earlier such findings 

previously discussed in the 1986 criteria document. 

Two of the more recent studies, by Linn et al. (1986) and Avol et al. (1987), add to the 

information reviewed in the 1986 U.S. EPA criteria document (U.S. Environmental 

Protection Agency, 1986) on lung function changes occurring in healthy childreh and young 

adults exposed to low concentrations of 0 3while exercising at rnoderate to heavy loads. 

Datn presented by Linn et al. (1986) in a controlled huinan study of healthy young adults 

exercising intermittently at heavy work loads have added more detailed concentrationresponse information at low 03concentrations ranging from 0.08 to 0.16 ppm. The 

03responsiveness of subjects in this study falls somewhere between that of subj.ects studied 

by McDonnell et al. (1983) and of those studied by Kulle et al. (1985) under similar 

exposure conditions (see Table 3-2). These subjects were also less responsive than the group , 

previously studied by Avol et a1. (1984), who were exposed to similar concentra.tions of 

03but with continuous exercise for 1 h. Although the authors of this report could not offer 

a definitive explanation for differences among these studies, they pointed out that individual 

biological factors such as the presence of asthma or clinical respiratory allergies and bronchial 

reactivity in individual subjects, as well as external factors such as ambient exposure history 

or differeiices in controlled exposure conditions during the study, might contribute to 

differences in cohort responsiveness to 0 3 . It is obvious that more research is needed to 

better define the possible reasons for the large variations in responsiveness to 0 3in 

individuals and the variations in group mean responsiveness across studies. 

Avol et al. (1987) presented data from a laboratory field study of healthy children (8 to 

11 years old) exercising continuously for 1 h in ambient air containing a mean 

Ogconcentration of 0.11 ppm. The same authors (Avol et a1., 1985a,b) previously studied 

adolescent subjects (12 to 15 years old) under a similar protocol, although the 

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3-14 
03concentration and exercise level were lower in the more recent study. No significant 

changes in respiratory function or symptoms were found in the group, probably because of 

the lower doses of 03 . Regression a.nalyses of individual data, however, suggested that 

individuals receiving high doses of 03had effects that were comparable to those found in 

adolescents and young adults, although no definitive comparisons could be made because of 

differing ambient exposure levels and large intersubject variability in responsiveness to 0 3 . 

This finding is also consistent with the controlled exposure study by McDonnell et al. 

(1985a,b) indicating that the effects of 0 3on lung spirometry in children were very similar' to 

those found in adults exposed under similar conditions, except that no significa.nt increases in 

symptoms were found in children. Therefore, based on the available pulmonary function 

data, young children and adolescents do not appear to respond differently to 0 3than do 

adults. 

A series of`papers describing the effects of 0 3on subjects greater than 50 years of age 

appeared between 1986 and 1989 (Bedi et al., 1988; Bedi and Horvath, 1987; DrechslerParks et al., 1987, 1989; Reisenauer et al., 1988) (see Table 3-1). 

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 iinportance of this study is 

that it dernonstrated a decline in response of considerable magnitude (AFEV 1of —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 to 76) subjects exposed 

to 0.45 ppm 03with a group of young adults studied under the same protocol (2-h 

intermittent exercise at 25 Llmin). The older subjects had substantially smaller changes in 

function than the younger subjects, both male and female. Changes in FVC 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 0 3exposure are reported in a 

second paper by Drechsler-Parks et al. (1989). 

Bedi et al. (1988) reported the results of a study in which older subjects were exposed 

to this same 03concentration (0.45 ppm) on three separate occasions. The responses were 

not reproducible from one exposure to the next. The group average did not change 

3-15 
appreciably between exposure series, indicating that even though the older subjects have more 

variable responses, they are less responsive to 0 3 , as a group, than younger subjects. 

Reisenauer et al. (1988) also studied a group of older subjects, age 55 to 74 years. 

These 03exposures were conducted at 0.2 and 0.3 ppm 0 3using a light intermittent exercise 

regime. There were no significant changes in FEV 1 0. For the 0.3 ppm exposures, 

however, the female subjects (n = 10) had a slight rise (13 %) in total respiratory resistance 

that was statistically significant. 

The implication of these differences in responsiveness to 0 3in 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. 

Four additional publications (Eschenbacher et al., 1989; Kreit et al., 1989; Koenig 

et al., 1988; Koenig et al., 1987) report the results of controlled human exposure studies on 

the effects of 03on asthmatics (see Tab1e 3-1). Also of interest is a new study of subjects 

with allergic rhinitis (McDonnell et al., 1987). 

Kreit et al. (1989) studied nine asthmatics exposed to 0.4 ppm 0 3for 2 h while 

perforniing intermittent exercise with a ventilation of about 53 L/min. A11 subjects had a 

history of physician-diagnosed asthma and were sensitive to methacholine. Medications were 

withheld for at least 12 h prior to exposure. Nine nonasthmatic subjects were also studied 

under the same protocol. Both groups of subjects had significant decreases in FVC, FEV1, 

FEV1 /FVC, forced expiratory flow at 25 to 75% of FVC (FEF25-75), and inspiratory 

capacity after 0 3exposure. The changes in FEVi, FEV1/FVC, and FEF~ 5-75were more 

negative in the asthmatics than in the normals (e. g. , A% FEV 1was —13.4 % in normals and 

—23.1 % in asthmatics). Specific airway resistance (SRaW) was not significantly increased in 

normals but was in asthmatics after 0 3exposure. A significant increase in SR aWalso 

occurred after air exposure in the asthmatics. The change in SR aWafter 03was more than 

twice that after exercise in air (ASR awair =+3.82, ASRawozone =+8:02 cm H20/L/s). 

Both groups experienced a similar relative increase in methacholine responsiveness after 

03exposure, expressed as a decrease in the provocative rnethacholine concentration that 

3-16 
causes a 100% increase in baseline SRa,. It is important to, note that these subjects 

underwent methacholine challenge both 90 min before and 90, min after exposure. 

It is not clear to what extent the preexposure challenge may have confounded the 

results, particularly because the nonasthmatics received a substantially larger dose of 

methacholine than the asthrnatics. Normal subjects appeared to have a depressed FEF25-7$ 

prior to exposure (=12% decrease after methachoiine challenge). There were no differences 

in 03-induced symptom responses between normals and asthmatics. 

A second report of this study (Eschenbacher et al. , 1989) additionally included a 

description of the effects of indomethacin pretreatment in 0 3-exposed normal subjects. The 

data for adult asthmatics were those reported by -Kreit et al. (1989). Indomethacin 

pretreatment in normals caused a marked decrease in 0 3-induced spirometry changes 

(OFEV 1— 03= —21. 5 % ; DFEV i— 03+ indomethacin = —10. 6 %) . However, there 

was also a surprising, but substantial, placebo effect, suggesting a possible behavioral 

component in 03response. Indomethacin, an inhibitor of cyclooxygenase pathways of 

arachidonic acid metabolism, had no effect on the increase in airway responsiveness caused 

by 03 . Indomethacin appears to primarily block the "restrictive" (i.e., decreased FVC) effect 

of 03and does not alter the bronchoconstrictive or airway reactivity responses. Of additional 

interest was the observation that "normal" subjects in the indomethacin study had an FEVi 

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 preexposure methacholine challenge. Further research is, therefore, needed to fully 

understand any potential differences in 0 3responsiveness between asthmatic and healthy adult 

subjects. 

The responses of adolescent asthmatics to 0.12 ppm and 0.18 ppm 0 3were tested by 

Koenig et al. (1987). The mouthpiece exposure sequence consisted of 30 min rest followed 

by 10 min exercise (minute ventilation [ VE] = 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 ppin 

03 . There were no significant changes in FEVlin either subject group. At 0.12 ppm 0 3 , 

there were no significant differences that could be attributed to 0 3in either asthinatics or 

normals. 

3-17 
Koenig et al. (1988) have also studied adolescent asthmatics (n = 10) and healthy 

adolescents (n = 10) exposed to either air, 0.12 ppm 03 , 0.3 ppm nitrogen dioxide (NO2

), 

or the combination of 03plus NO2. 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 h prior to exposure. In the asthmatics, an 11 % decrease in 

FEF50% was observed after 0.12 ppm 0 3exposure. One of the subjects had an exceptionally 

large decrease in FEF50%of —60%, which occurred approximately 20 min after the end of 

exposure. This same subject did not have a large change in FEF 50%when exposed to 

03 plus NO2, suggesting that the response of this individual to 0 3may have been anomalous. 

There were no other responses attributed to 0 3in this study, either in normal or asthmatic 

subjects. The authors tentatively suggested that adolescent asthrnatics may be slightly more 

responsive to these low levels of 0 3 . 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 0 3sensitivity. These allergic subjects had 

airway responses to histamine that were similar to a comparable group of nonallergic 

subjects. Exposure to 0.18 ppm 03for 2 h with heavy intermittent exercise caused increased 

responsiveness to histamine and a decrease in several spirometric variables. The only 

apparent difference between the allergic subjects and previously exposed nonallergic subjects 

was a significant increase in airway resistance in the allergic subjects. These data on allergic 

and asthmatic subjects suggest that both of these groups have a greater rise in airway 

resistance after 03exposure than do normal subjects. The relative order of airway 

responsiveness to 03is normal < allergic < asthmatic. 

Between 1987 and 1989, a series of reports were presented or published concerning a 

sttidy of apparent seasonal variation in 0 3responsiveness in residents of Los Angeles (Avol 

et al., 1988; Hacl:ney and Linn, 1989; Hackney et al., 1989; Linn et al., 1988) (see 

Table 3-1). The definitive report of this study is the journal publication by Linn et al. 

(1988). From a large number of subjects tested for 0 3responsiveness, 12 responsive and 

13 nonresponsive subjects were selected to participate in further testing. Cbaracteristics of 

the subjects are presented below: 

W-1 
Gender Age Health Status Mean •AFEVi 

Nonresponders 8M/5F 5> 30 All Normal + 1% 

Responders 5M/7F 2> 30 4 Normal —12.4 % 

6 Atopic 

2 Asthmatic 

In all tests, subjects were exposed to 0.18 ppm 0 3during 2 h of intermittent heavy 

exercise (ventilation = 35 L/min/m2body surface area [BSA]) at 35 °C and 35% relative 

humidity (RH). These 25 subjects participated in two more pairs of exposure to 0 3and 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 follow-up 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 follow-up studies in late summer 

and winter. This suggested the possibility that ambient oxidant exposure during the summer 

months produced an "adaptation" response that persisted for several months. This suggestion 

was further strengthened when a reduced number of subjects were exposed to 0 3again, one 

year later. At this time, the responsive subjects appeared to regain their sensitivity to 

03exposure. The mean absolute changes in FEV 1for the four exposures in the responsive 

subjects were —385, —17, +16, —347 mL respectively for the spring, fall, winter, and 

spring tests respectively. Corresponding changes for the iionresponders 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 

03exposures 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. (1989) 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 syrnptomatic coinplaints when 

exposed to "smog". The authors suggested that allergy or atopy may be a risk factor for 

excess response to 0 3although other studies have indicated that increased airway reactivity is 

not predictive of 03responsiveness. They further speculated that nonresponders could be at 

gmLtm 
increased risk for chronic health effects of cumulative ambient 0 3exposure because they 

would be less likely to avoid such exposures because of their lack of symptomatic complaints. 

Controlled human exposure studies reviewed earlier in the 1986 U.S. EPA criteria 

clocument have suggested that some impairment of exercise performance may be associated 

with 03exposure. 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 0 3concentrations > 0.18 ppm. 

Studies by Gong et al. (1986) and by Schelegle and Adams (1986) substantiate these earlier 

findings, whereas a third study by Linder et al. (1988) suggests that small decrements in 

maximal exercise performance may occur at O, concentrations <0.18 ppm (see Table 3-1). 

Gong et al. (1986) found that maximal performance tested after exposure of endurance 

athletes continuously exercising at heavy work loads ( VE= 89 L/min) for 1 h in a hot 

environment was impaired in 0.20 ppm 0 3 . This level of 03exposure also reduced 

pulmonary function and enhanced respiratory symptoms and airway responsiveness to 

histamine. Maximal performance was not impaired after exposure in 0.12 ppm 0 3 , despite 

sma11 but significant group mean decrements (5.6 %) in FEV 1 . Sirnilarly, Schelegle and 

Adams (1986) found that exercise perforrriance, as determined by completion of the exposure 

protocol, was impaired following exposure of endurance athletes who were continuously 

exercising at heavy work loads (VE= 87 L/min) for 1 h at 03concentrations >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 3 . 

The effect of 0 3inhalation on performa.nce of maximum exercise tests was also studied 

by a group of Swiss investigators (Linder et al., 1988). Twenty-four subjects (12M, 12F) 

were studied while performing maximal incremental exercise tests. The maximum exposure 

duration was 28 min and the minimum was 16 min. The tests were performed in clean air, 

0.07 ppm 03 , and 0.13 pprn 03in an environmental chamber (24 °C; 50% RH). Small, but 

significant (t-test), increases (2%) in FEV 1 owere observed after clean air exposure. Except 

for women exposed to 0.13 ppm (-1.4%), no changes in FEV 1were observed with 

03exposure. 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 pprn (p < 0.05, t-test). 

During the tests conducted at 0.13 ppm, there was also a small decrease (2.5 to 5%) in 

3-20 
anaerobic threshold, defined as the workload at which the venous lactate concentration 

exceeded 4 mM. It is not clear to what extent the exercise performance test results may 

reflect behavioral responses to the odor of 0 3 . 

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 i , it appears that no significant 

changes would be detected by an appropriate statistical a.nalysis (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 concentrations and brief exposure durations 

(maximum 28 min) and because they appear to be out of line with previous studies of 

exercise performance during 0 3exposure, it is important to determine if these qbservations 

can be verified. 

The data currently available indicate that reduction in exercise performance may occur 

in many well-conditioned athletes after performing continuous heavy exercise for 1 h at 

03concentrations >_0.18 ppm. These athletes are capable of sustaining very high exercise 

VE(i.e., > 80 L/min) for 1 h. Any performance decrements occurring at 0 3concentrations 

<0.18 ppm are less certain and need to be verified. It must be noted, however, that 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 03from physiological or behavioral effects caused by other conditions in the environment. 

Studies utilizing longer exposure durations, particularly at lower levels of exercise, were 

not previously reviewed in the 1986 U.S. EPA criteria document. Among the newer studies, 

two (Folinsbee et al., 1988; Horstman et al., 1989, 1988) address the effects of 0 3exposures 

for durations > 2 h(see Table 3-1). The first of these was designed to determine the effects 

of prolonged exposure to the present level of the 1-h NAAQS for 0 3(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 0 3for a total of 6.6 h. During the exposure, the 

subjects exercised for six periods of 50 min each; each exercise period was followed by 

3-21 
10 min of spirometry testing and rest. An additiona135 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 0 3resulted in progressively larger changes in 

respiratory function and symptoms with time. By the end of 6.6 h of exposure, group mean. 

changes were as follows: FEV ihad decreased 13.0%, FVC had decreased 8.3%, and 

FEF25 75% had decreased 17.4%. On forced inspiratory tests, forced inspiratory v,ital 

capacity and forced inspiratory volume in 0.5s were decreased 12.6 and 20.7%, respectively. 

Respiratory symptoms of cough and pain on deep inspiration increased with the increasing 

duration of 03 exposure. There was also -a marked increase (about twofold) in airway 

responsiveness to methacholine following 0 3exposure. 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 E ~: 60 L/min) in much higher 03concentrations (> 0.2 ppm) for shorter 

durations (i.e., <2 h). 

The need for additional concentration-response information led to a subsequent study 

using the same 03exposure protocol. Twenty subjects were exposed for 6.6 h to four 

03 concentrations (0.0, 0.08, 0.10, a.nd 0.12 ppm) in random order. The results of this 

study were reported, in part, at the 1988 U.S.-Dutch symposium (Horstman et al., 1989) and 

at the 1988 Annual Air Pollution Control Association Meeting (Horstman et al., 1988). The 

ventilation in this study was slightly lower than in the first study, averaging .38.9 L/min. The 

FEVI.Odecreased 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 u.pon deep breath, 

a typical symptom of acute 0 3exposure. 

The study by Folinsbee et al. (1988) is the first clinical study to demonstrate increased 

airway reactivity to inhaled bronchoconstrictors in subjects exposed to low 0 3concentrations 

for prolonged periods of time. Other studies reported in the recent literature have identified 

these effects in humans exposed to 0 3for shorter durations (see Table 3-1). 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 0 3for 2 h while undergoing 

3-22 
heavy (VE= 64 L/min) intermittent exercise. Seltzer et a1. (1986), in a study of 10 healthy 

individuals exposed for 2 h to air and to either 0.4 or 0.6 ppm 0 3while undergoing moderate 

intermittent exercise, observed an increase in the number of neutrophils in bronchoalveolar 

lavage (BAL) fluid 3 h after 0 3exposure. Furthermore, they observed an increase in airway 

reactivity to methacholine following 03exposure and their data were suggestive , of an 

association between the degree of inflammation and the increase in airway reactivity. 

A series of reports by Koren et al. (1989a,b; 1988a,b) described the inflammatory and 

biochemical changes in the airways consequent to 0 3exposure (see Table 3-1). In these 

studies, subjects were exposed to 0.40 pprn for 2 h while performing intermittent exercise 

(15 min exercise, 15 min rest) at a ventilation of 70 L/min (35 L/min/m 2BSA) (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, BAL was performed about 18 h after the 0 3 exposure. Standard lung 

function tests were also performed before a.nd after exposure. A mean decrease in FEV 1of 

960 mL after 03exposure was reported. An eightfold increase in polymorphonuclear 

leukocytes (PMNs) was observed after 0 3exposure, confirming the observations of Seltzer 

et al. (1986). A twofold increase in protein, albumin, a.nd immunoglobulin G were indicative 

of increased epithelial permeability as previously suggested by the technetium-labeled 

diethylene triamine pentacetic acid (DTPA) clearance studies of Kehrl et al. (1987) . In 

addition to confirmation of these previous findings, Koren et al. (1989b) provided evidence of 

stimuiation of fibrogenic processes including increases in fibronectin (6.4 x), tissue factor 

(2.1 x), Factor VII (1.8 x), and urokinase plasminogen activator (3.6x). There was a 

twofold increase in the level of prostaglandin E 2and a similar elevation of the complement 

component C3a. Levels of the leukotrienes LTC4and LTB4were not affected. Koren et al. 

(1989a) reported that an inflammatory response, as indicated by increased levels of PMNs, 

was also observed in BAL fluid from subjects exposed to 0.1 ppm 0 3for 6.6 h(same 

protocol as Folinsbee et al., 1988). 

Further evidence supporting the hypothesis that cyclooxygenase products of arachidonic 

acid metabolism (prostaglandins, thromboxane) may piay a role in 0 3-induced spirometry 

cha.nges comes from a study by Schelegie et al. (1987). These investigators demonstrated a 

significant attenuation of decrements in FVC and FEV 1 owhen subjects were treated with the 

3-23 
cyclooxygenase inhibitor indomethacin prior to 0 3exposure. Subjects were exposed to 

0.35 ppm for 1 h of continuous exercise (60 L/min); FEV 1.0decreased 26.3% on the 

no-drug day, but only 10.6 % after indomethacin pretreatment. 

The above studies indicate that the inflammatory process caused by 0 3exposure is 

promptly initiated (Seltzer et al., 1986) and persists for at least 18 h(Koren et al., 1989b). 

The time course of this inflammatory response and the 0 3exposures necessary to initiate it, 

however, have not yet been fully elucidated. Furthermore, these studies deinonstrate that 

cells and enzymes ca.pable of causing damage to pulmonary tissues were increased and the ' 

proteins that play a role in the fibrotic a.nd fibrinolytic processes were elevated as a result of 

03exposure. 

Graham et al. (1988) showed an increase in PMNs in nasal lavage fluid collected from 

subjects exposed to 0.50 ppm for 4 h at rest. There was a 3.5-fold increase in nasal PMNs 

immediately after exposure and this increased further (6.5-fold) by the following day (i.e., 

20 h later). This study suggests that a nasal inflammatory response may serve as a qualitative 

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 eight healthy subjects 

who endured heavy exercise for 2 h in 0.4 ppm 0 3 . Kehrl et al. (1989) reported results from 

an additional 16 subjects studied in the same manner. For the combined group of 24 subjects 

exposed for 2 h to 0.40 ppm 03 , the average rate of clearance of technetium-labeled DTPA 

was 1.08 %/min. This clearance rate was some 60 % faster than that observed after air 

exposure. The average 03-induced decrement in FVC in these subjects was —10%. This 

study confirms that clearance of technetium-labeled DTPA is accelerated after 0 3exposure 

and, in conjunction with the Koren et al. (1988a,b; 1989a,b) observations, strongly suggests 

that this accelerated clearance is due, in part, to an increased epithelial permeability within 

the lung. These changes in permeability are most likely associated with acute inflammation 

and could potentially allow better access of inhaled antigens and other substances to the 

submucosa. Results from studies of these endpoints at lower 0 3levels have not been 

reported. 

These observations by Koren, Kehrl, and co-workers have raised the question of 

whether acute inflammation occurs following exposure to low levels of 0 3for prolonged 

3-24 
periods of time (> 2 h). Results from studies determining if these newly identified 0 3effects 

are occurring at low 03concentrations (i.e., <0.12 ppm) remain to be more fully reported 

and evaluated. This information will improve our understanding of the nature of 

inflammatory responses, including the biochemical and molecular changes in the lung, that 

occur in 03-exposed subjects. 

Another series of papers by Gerrity and co-workers (Gerrity, 1987; Gerrity et al., 1988; 

Gerrity a.nd McDonnell, 1989) examining 0 3uptake in _the respiratory tract have important 

implications for modeling the health effects of. 0 3exposure in humans and for extrapolating 

data from animals to humans (see Table 3-1). 

Gerrity et al. (1988) studied 18 healthy young males to determine the fractional uptake 

of 03by the upper respiratory tract (URT), excluding the larynx, and by the lower 

respiratory tract (I.,RT), including the larynx. In order to measure 0 3concentrations during 

the breathing cycle, a. chemiluminescent 03analyzer 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 0 3concentration were 

used to compute the fractional uptake of 0 3in the URT and LRT. The investigators studied 

the effects of cha.nges in 0 3concentration (0.1, 0.2, 0.4 ppm), breathing frequency (12 and, 

24 breaths per minute) and mode of breathing (nasal, oral, oronasal). The differences 

between the various treatment conditions were small; the average URT uptake was about 40 % 

and average LRT uptake was about 91 %(of the 0 3that reached the larynx), resulting in an 

average total respiratory tract uptake of approximately 95 %.. (In other words, of the 

03entering the URT, about 40 % was removed. Of the remaining 60 % that reached the 

trachea, 91 % was removed. Total uptake is therefore 40 %+(0.91 x 60 %) = 95 %.) 

Increased frequency of breathing caused a decreased fractional removal of 0 3in both URT 

and LRT, presumably because of decreased residence time in the airway and increased flow 

rate. The lowest fractional removal of 0 3in the URT occurred during nasal breathing. The 

differences between nasal and oral or oronasal breathing, however, were very small. The 

lack of significa.nt differences between nasal and oral breathing on 0 3 -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 0 3uptake as much as previously 

expected. 

3-25 
In a second paper, Gerrity a.nd McDonnell (1989) reported the influence of the 

03-induced change in breathing pattern on the 03 uptake efficiency. Subjects were exposed 

to 0.4 ppm 03 during continuous 60 min 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 FEVl. The change in breathing pattern was accompanied 

by a 9% reduction in the LRT 0 3uptake efficiency (fractional LRT uptake decreased from 

68 % to 62 %). Total 0 3uptake (about 80 %) was only reduced about 4% because there was a 

slight increase in 03uptake in the URT. The reduction in LRT 0 3uptake was correlated 

with the decrease in tidal volume, suggesting that an increased depth of inspiration increases 

the dose delivered to the LRT. The 03uptake "efficiencies" reported in these two papers are 

not strietly comparable because the methods used to make the calculations of 0 3uptake 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 0 3delivery to the lower respiratory tract. 

Gerrity (1987) described a model of nasopharyngeal uptake of 0 3using data from 

various animal species, including humans. The conclusion reached in this analysis was that 

nasopharyngeal 03uptake decreases with increasing flow but that there was also a 

considerable species variation in uptake (see Section 3.1.3.3 and Table 3-6). 

The above observations of Gerrity and co-workers have important implications for 

interpretation of heavy exercise studies: Increased tidal volume increased LRT 0 3delivery, 

but there may be a limit beyond which inereases in tidal volume will not cause increased LRT 

Ogdelivery. 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 

predieted model, making it possible to develop dose-response information from the wealth of 

controlled human exposure studies that have already been published. The current likelihood of 

making animal-to-human extrapolations based on this information and on the comparison of 

respiratory tract uptake of 0 3across different mammalian species is discussed later in 

Section 3.1.3.3. 

3-26 
3.1.2 I+ield and Epidemiological Studies 

Field and epidemiological studies reviewed earlier in the 1986 Criteria Document (U.S. 

Environmental Protection Agency, 1986) reported a variety of results concerning associations 

between exposures to ambient 0 3and various measures of respiratory effects. The results of 

many of these studies were found to be directionally consistent with the findings of controlled 

human exposure studies, especially those providing reasonably good evidence for associations 

between ambient 0 3exposures and acute pulmonary function decrements. Results of other 

epidemiology studies evaluating other health endpoints, e.g. exacerbation of asthma or other 

chronic lung diseases, were found to be more difficult to interpret due to methodological 

limitations, but some of these latter studies tended to point toward possibie increases in 

symptom aggravation or changes in lung function of asthmatic sub_jects being associated with 

increased total oxidant levels, ambient 0 3concentrations, or interactions between ambient 

03levels and temperature. However, no consistent pattern of findings for aggravation of 

symptoms or iung function changes emerged for patients with other types of chronic lung 

disease. Newer field and epidemiology studies (summarized in Table 3-3), as with the older 

literature, continue to provide sornewhat mixed results across various health endpoints 

measured—with most progress having been made with regard to provision of further 

information concerni.ng exposure dynamics related to the induction of pulmonary function 

decrements by short-term ambient 0 3exposures. 

Included among the newer studies published since 1986 are reports by Raizenne and 

coworkers on several aspects of field studies of children in two summer camps in Ontario 

(Raizenne et al., 1987; 1989), one at Lake Couchiching (LC) about 100 km north of 

Toronto, Ontario, and one at, a Girl Guide camp on the north shore of Lake Erie. In the LC 

study (Raizenne et al., 1987), the strongest association between iung function and 

environmental variables was found in nonasthmatics, with FVC decrements correlated 

(p < 0.01) with 24-h lag functions for average SO 4 — , partilces <2.5 μm (PM2 5), and 

temperature. The association of peak expiratory flow rate (PEFR) with unlagged 1-h 0 3was 

statistically significant and the average slope of the regression line was —2.7 (mL/s/ppb). 

Temperature was significantly associated with all lung indices in nonasthmatics but not in 

asthmatics. The average slope of PEFR for teinperature in nonasthmatics was —21.7, a 

much stronger association of PEFR with temperat'ure than with 0 3 . Coefficients of variation 

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3-32 
(CV %) were stable across the daily morning and evening tests of pulmonary function. 

Although 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 iindoor (as on rainy days) versus outdoor activity estimated (i.e., actual 

exposure as well as proportion of higher versus lower exercise 1evels). 

Raizenne et al. (1989) also presented preliminary data from a study of the effects of air 

pollution on girls aged 8 to 14 who attended one of three consecutive 2-weelc sessions of the 

Girl Guide camp on Lake Erie (June 29 through August 9, 1986). The health status of each 

camper participati.ng in the study (112 of 145) was characterized by questionnaires completed 

by parents, by bronchial challenge with methacholine (positive responses were classified as 

Mch+ and negative responses were classified as Mch—), 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 mea.n responses on "control" days (the 

latter defined as days with a 1-h 0 3maximum of <90 ppb; SO4—< 15 ,ug/m3 ; and sulfuric 

acid, H2SO4, <10 μg/m3). Also, lung function on the morning following an 0 3episode 

versus the average function on controf days was examined. 

Maximum decrements of 3.5 % and 7% for FEV 1 oand PEFR, respectively, were 

reported to be associated with four distinct air pollution episodes in which 0 3 , H+ , and 

SO4 —were all elevated. Only FEV 1 ochanges were statistically significant and only on 

2 episode days (one each in Camp Sessions 1 and 2). For each camp session, the mean 

values for FVC, FEV 1 0, and maximum mid-expiratory flow rate (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 PEFR. The largest FEV t oand 

PEFR decrements were observed in methacholine responsive (Mch+) children the morning 

after (July 26) the highest 0 3level measured (July 25) during the study. In Mch — children, 

however, the FEV 1 ochange was positive and the PEFR change was negative, both on July 

25 and July 26. In Camp Session 3, improvement in both FEV 1 oand PEFR were noted. 

The authors postulated the exposure of campers in Session 3 to a regional episode prior to 

their arrival in camp, with recovery occurring while at cainp. No hypothesis was put 

forward to explain the positive FEV l ochange in Mch— children on the day of the highest 

peak 03level and on the day following. The lack of an aggregate analysis and the presence 

3-33 
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 for the 

effects of 03 or of air pollution episodes on pulmonary function. 

On Ju1y 25, when the 1-h 03 1eve1 was elevated (143 ppb), 12 subjects performed 

pre- and postexercise spirometry (exercise level and resulting VEnot estimated). For this 

subset of subjects, postexercise FVC and FEV i owere observed to increase on control day 

tests and to decrease on the episode day (results on the episode day were compared with the 

mean pulmonary function test results for all control days). The function changes did not 

attain statistical significance, however (Raizenne et al., 1989). 

During the study of girls attending the Lalce Erie residential camp, investigators 

(Raizenne and Spengler, 1989) 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 0 3and H2SO4 , the slopes of function 

(i.e., peak expiratory flow rate, PEFR) versus pollutant did not differ from zero when the 

data were adjusted for dosimetry. Adjusted data for FEV 1 owere not reported. 

From a field study they conducted in 1984 at a YMCA summer camp (Fairview Lake) 

in northwestern New Jersey, Spektor et al. (1988a) have reported associations between 

0

3and variations in respiratory functions for 91 children attending camp for at least 2 weeks. 

Average slopes for the regressions between 0 3concentrations and functions were significantly 

negative (p < 0.05) for FVC, FEVl o, 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 (temperature-humidity 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 differences in FEV t ochanges between girls and boys. Little or no 

eomparable effect of a heat stress component was seen in boys. Activity levels were not 

estimated, so that the V Ecomponent of the responses was not estimated for individual 

children or for cohort subsets. 

As reported by the authors, multiple regression analyses indicated that the 

Ogconcentration in the hour preceding spirometry, the curnulative daily 0 3exposure during 

3-34 
the hours between 9:00 a. m. and the function measurement, ambient temperature, and 

humidity were the most explanatory environmental variables for daily variations in pulmonary 

function, with the 1-h 0 3concentration having the strongest influence. The authors 

calculated predicted average functional decrements from the average slopes of the base data 

set (Table 3-1, 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 0 3at the current standard of 

120 ppb. Of the 91 children studied, 33 (36%) had individually statistically significant 

FEV1 oresponses, with a.n average coefficient in that subset of —2.97 mL/ppb, or about a 

16% decrement—again assuming linearity—at 120 ppb 0 3 . The values for the 2-week subsets 

are generally consistent directionally with 0 3concentrations in the respective 2-week periods 

and the total period. Likewise, slopes for data truncated at < 60 ppb and < 80 ppb 0 3show 

general directional consistency with the 0 3concentration data, except for FEF25-75• 

Several considerations should be noted. Ozone and temperature are statistically 

correlated in this study (r = 0.37), with evidence of effects of heat stress on 0 3-associated 

decrements in function. If the respiratory effects depend nonlinearly on interactions between 

temperature (or THI) and 03 , this may confound interpretation of the effects of 0 3 . Data 

were truncated at 60 and 80 ppb a.nd the conclusion was drawn that 0 3 -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 well-conducted study would be strengthened, 

however, by additional analyses. As reported, calculated decreinents at the level of the 

current standard should be interpreted cautiously. 

Spektor et al. (1988b) conducted a field study of the effects of 0 3in 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. a.nd 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 E) for each exercise period was estiinated from the subject-reported heart-rate data, 

3-35 
calibrated from heart-rate data recorded from indoor treadmill exercise at a pace similar to 

the outdoor exercise level. 

For each subject, on each exercise day, pre- and postexercise function rneasurements 

were taken, and changes in function were determined for FVC, FEV i o, (FEV1 o/FVC), 

PEFR, and FEF2,5_75. Subject-specifc exposures were estimated from duration of exercise, 

mean 03concentration during the exercise period, VE, and the tidal 03inhaled during 

exercise. Pollutants and environmental variables measured were 0 3 , S02, nitrogen oxides, 

ambient aerosols (PM15and PM2 5), aerosol acidity and other fine-particle ions, temperature, 

humidity, and wind speed and direction. Pulmonary function variables were regressed on 

mean Ogconcentration during exercise for each subject, as well as against the 

03concentration during exercise on the preceding day. Interactions of other environmental 

variables with 03were tested. 

All pulmonary function indices showed significant (p < 0.01) 0 3-associated 

decrements. No clear effects from other variables on the effects of 0 3were seen. Mean 

decrements were reported as smaller in 10 subjects with VE> 100 L/min than those in 

10 subjects with cV Fof 60 to 100 L/min or those in 10 subjects with VE< 60 L/min. The 

decrements were reported to be about twice as large as those seen in 1- to 2-h chamber 

studies in which V Elevels were comparable. No association was found between preexercise 

lung function and mean 0 3concentration during exercise on the preceding day (no evidence 

of persistence of 0 3effects). No symptomatic responses were reported. A.nalysis of lung 

function changes for ventilations of 50 to 80 L/min was reported by the authors to indicate 

that the influence of VEon lung function decrements peaks at about 80 L/min: 

This study substantiates the effects of 0 3on pulmonary function in populations engaging 

in continuous exercise outdoors for short periods of time (15 to ca. 60 min; average duration 

of ca. 30 min). The study further suggests that pulmonary function decrements observed 

with ambient exposures to 03at 0.12 ppm or somewhat lower may be larger than those seen 

'With comparable 03exposure concentrations and exercise conditions in controlled human 

exposure chamber studies, possibly due to potentiation of 0 3effects by other ambient 

cofactors. 

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 Harriman, TN, 

3-36 
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, FEVo 7$ , MMEF, and V75%were regressed (ordinary least squares model) on the 

1-h maximum 03concentrations and on the 24-h-average fine particles (FP) and FP-SO 4— 

concentrations. Ozone concentrations ra.nged from 3 to 63 ppb during the study. 

Concentrations of other pollutants (S0 2, NO2, total suspended particulate (TSP), inhalable 

particles (IP), respirable suspended particles (RSP), and FP) were not reported. Slopes of all 

four lung function-03regressions were significantly 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 0 3concentrations present during the study detract from plausibility. 

Kinney et al. (1988) later published an interpretive evaluation of five epidemiological 

studies of the effects on lung function of acute exposures to 0 3 . In that review, they 

compared the coefficients of 0 3-associated lung function declines reported in those 

epidemiology studies with modeled exposure-response relationships for such effects derived 

from a synthesis by Hazucha (1987) of results from controlled huinan exposure studies. 

Hazucha (1987) modeled the effects of exercise-related ventilation rates ( VE) in potentiating 

the effects of 0 3on pulmonary function, using pooled data from 2-h chamber studies of 

healthy young adults exercising intermittently. Kinney' et al. (1988) reexpressed the data of 

Hazucha (1987) in units consistent with the epidemiologic study results (assuming a linear 

relationship between lung function decline and concentrations up to 100 ppb and using 

baseline 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 the controlled studies). Kinney et al. (1988) 

concluded that the "effective" exposures in the epidemiologic studies were cumulative over 

longer periods (from 8 to 12 h versus the 2-h exposures used to generate the controlled 

exposure data analyzed by Hazucha). 

The Kinney et al. (1988) analysis provides further results suggesting that possibly larger 

lung function decrements occur with ambient 0 3exposures than those seen in controlled 

human exposure studies. However, caution is warranted given several considerations. For 

3-37 
one, no justification was given for the use of the linear model and the transforrnation of data 

from Hazucha (1987), who had used a quadratic model. At concentrations :5100 ppb, a linear 

model would tend to overestimate lung fiinction decrements if the quadratic rnodel is actually 

more appropriate, whereas at higher 0 3concentration's the linear model would underestimate 

lung functiion deeline in comparison to a quadratic niodel. Unfortunately, although the upper 

eiid of the range of 03concentrations measured in the epidemiologic studies reviewed partially 

overlaps the lower end of the range used in the controlled studies modeled by Hazucha, the 

mean concentrations in the respective epidemiologic studies from which data were used were 

< 100 ppb—thereby not allowing for a direct comparison of the magnitudes of the effects seen 

with ambient versus controlled •exposures across a fuller range of exposures of interest (e.g., 

0.05 to 0.15 ppm 03). Also complicating the comparison are possible differences in exposure 

durations—leading, in fact, to the postulation by Kinney et al. that the effective 0 3exposures 

~ 

(including lower ambient 03levels) were likely to have been more prolonged (8 to 12 h) in 

the epidemiology studies than the exposure duration (2-h) used in the controlled exposure 

studies. 

Lioy and Dyba (1989) also reported a new analysis of previous data suggestive of 

prolonged 03exposures being the effective exposures in an earlier field study conducted in 

Mendham, NJ, as reported on by Bock et al. (1985) and Lioy et al. (1985). In this case, Lioy 

and Zyba used a time-activity pattern analysis for a hypothetical typical camper that would 

liave experienced a usual daily activity schedule analogous to children participating in the 

Mendham summer camp study. They found that the time-activity analysis indicated a 

likelihood that periods of increased exercise for the cainper would have likely occurred over 

prolonged periods of time (several hours) during which ambient ozone levels were elevated 

(i.e., above 0.10 to 0.12 ppm). Evaluation of the total estimated 0 3dosages likely 

experienced on successive days of a 4-day 0 3episode further led them to hypothesize that the 

accumulated, multihour doses from prolonged daily exposures to ambient 0 3may have been 

niost importaiit in producing the pulmonary function decrements earlier reported for the 

Mendham study, rather than next day residual effects being due to peak 0 3concentrations. 

Vedal et al. (1987) reported data from an 8-ino panel study of symptoms and 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 

cm 
was strongly associated with any of the environmental variables, which. included peak 1-h 0 3 , . 

NO2, S02, and CoH, and daily temperature. Level of PEFR on the previous day was the 

strongest predictor of daily PEFR. True exposures to 0 3and other pollutants may have been 

misspecified, because 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 0 3during this schoolyear study were very low, with the daily maximum 1-h levels ranging from 0 to 129 ppb, 

with a mean of 32.4 ppb. 

Results for the 1980-1981 school year have been recently reported by Dockery et al. 

(1989) 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 

S02concentrations measured in the six cities. Lung function was determined at school by 

spirometry, and a respiratory illness and symptom questionnaire was completed by each 

child's parents. Pollutants measured included TSP and particles <15 μm (PM 1$) and PM2 5 , 

03, NO2, and S02. Continous measurements (hourly values) of S0 2, NO2, 03 , and 

meteorological variables, as well as daily values for varrious particle measures (e.g., TSP, 

PM15 , PM2 5 , etc.), were taken. Monthly means for each pollutant were calculated from 

daily means, and an estimate of air pollution exposure during the previous year was obtained 

for each child by averaging the monthly means for a given city for the 12 mo preceeding the 

child's spirometry test. All pollutant concentrations were highly positively correlated with 

each other in all cities, except for, 0 3 , which was highest in those, cities with low levels of the 

other pollutants. The pulmonary function parameters measured were. FVC,, FEVi.o ~ 

FEVo 75 , and MMEF. Five respiratory iilness or symptom categories were also considered: 

bronchitis, cough; chest illness, wheeze, and asthma. 

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 

poilution—TSP, PM 15 , and PM2 5—but only associations with PM iswere statistically 

significant. Sulfur dioxide, which showed correlation with the particulate measures, was 

3-39 
much more weakly associated than particles with the respiratory symptoms. The association 

of NO2 with respiratory symptoms was also weak. There were negative associations of 

03with cough and chest illness, but annual 0 3showed a strong positive association with 

asthma and hay fever (in contrast to negative associations of these symptoms with-all other 

measured air pollutants). No association was found between air pollutant levels and the 

pulmonary function measures, including FEV0.75and MMEF, which are more sensitive 

measures of small airway impairment than FEV i oand FVC. This led the authors to 

conclude that the increased rates of illness observed for some pollutants were not likely 

associated with permanent loss of pulmonary function—at least in preadolescent years. 

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 1976-1983) for 

examining correlations between environmental varriables and hospital admissions for 

79 acute-care hospitals in southern Ontario, Canada. Pollutant concentration data for 

0

3 , NO2, sulfur dioxide (S02), coefficient of haze (CoH), and sulfate (SO 4 !) were collected 

at 17 sampling stations located across a 280-mile corridor between the Windsor and 

Peterborough areas of Southern Ontario. Correlations were exarnined for relationships among 

environmental variables and between environmental variables and three categories of hospital 

admissions for winter (January-February) and summer (July-August), i.e. for total respiratory 

admissions (TRA), TRA minus asthma (TRA—A), and nonrespiratory admissions, separately. 

The authors concluded that an association exists in southern Ontario between 0 3and 

TRA and TRA—A 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 3and adrnissions to children's 

hospitals or emergency room visits in Los Angeles, where 0 3levels are higher than those in 

southern Ontario. They concluded, as well, that aerosol SO4 –levels explain the highest 

percentage variance in TRA from pollution in summer, but are not correlated with TRA in 

winter. They also concluded that 0 3and SO4 –may be surrogates for one or more other 

species that travel with them in summer but not in winter, such as hydrogen ions (H +) in the 

fne-particle range. Lastly, it should be noted that Bates and Sizto (1987) specifically tested 

the maxirnal 8-h 03average for correlation' with TRA. The Pearson correlation coefficient 

was not affected by substitution of the 8-h value in place of the mean of the hourly 

3-40 
03maxima previously used. The correlation between the 1-h and 8-h 0 3maxima across all 

monitoring stations was 0.986. 

Using the same methodology, Bates and Sizto (1989) examined aerometric and hospital 

admissions data for June, July, and August 1983 and for June in the years 1979 through 1985 

because June 1983 was observed to have 0 3levels 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 w.ith 0 3-associated excess 

admissions reported earlier. The authors concluded that these findings cast doubt "on the 

primacy of 03as the cause" of increased admissions, and that there are reasons against 

attributing excess admissions either to 0 3or SO4 — . 

Although asthmatics are not unequivocally more sensitive to 0 3than nonasthmatics, 

neither have they been shown to be less sensitive (U.S. Environmental Protection Agency, 

1986). Therefore, the findings of an epidemiologic study of asthmatics reported by Gong 

(1987) are of particular interest. Gong (1.987) 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 analyses were 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 0 3and average symptom scores, asthma 

medication index (AMI), and day and night PEFR across subjects showed weak, 

nonsignificant relationships. These daily outcome variables were compared for days with 

maximum 1-h-average 0 3in three ranges: G 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 indicated 

the lack of a significant overall relationship between 0 3(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 

3-41 
significantly negative relationships to respiratory variables, but only the effect of trees was 

considered clinically relevant. Temperature and humidity showed no significant effect on the 

respiratory variables in this study. 

Although there was no significant overall effect of 0 3on respiratory variables in the 

83 asthmatic subjects, multiple regressioii analysis of subjects whose 0 3coefficients on 

various days were in the top quartile for dependent variables (respiratory measures) showed 

significant and consistent effects of 0 3on day t and the previous day (t-1). 1'vlultiple 

regression testing of subsets for associations of symptom score or day or night PEFR on the 

same day's 03and the previous day's value of the same responses showed highly significant 

03coefficients for•all three respiratory nieasures. 

The clinical significance of responses in symptom scores and day and ni,ght PEFR was 

evaluated for all subjects by individual regression analyses. No subject had evidence of 

significant worsening of symptoms attributable to 0 3during the study. Adult subjects with 

high scores in fatigue, hyperventilation, dyspnea, congestion, and rapid breathing in the 

Asthma Symptom Checklist had more negative slope coefficients for 0 3than 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 differences in ambient ozone concentrations since the 

test scores were similar during relatively low (first test) a.nd high (second test) ozone days. 

The significance of the psychological results is unclear at this time and will be the subject of 

further analyses" (Gong, 1987). 

Lastly, it should be noted that a reanalysis by Schwartz et al. (1988) of the Los Angeles 

epidemiology study of student nurses earlier reported by Hammer et al. (1974) confirmed the 

Hammer et al. results showing oxidants to be significantly associated with eye discomfort and 

cough. However, earlier reported associations between oxidants and headache or chest 

discomfort were not confirmed. The relationship of oxidants to eye irritation has been 

previously reported by others and appears to be related to peroxyacetal nitrate (PAN) rather 

than 03 . Cough has been shown, however, to be a respiratory symptom related to 0 3 , and 

the present reanalysis (using logistic regression models and time-series analyses controlling 

for autocorrelation effects) conf rmed the presence of an apparent threshold for "cough" 

3-42 
earlier found by the "hockey-stick" function analysis done by Hammer et al. (1974). The 

upward flexure point in the dose-response curve occiirs near the value reported by Hammer 

et al. (ca. 20 pphm total oxidants)—a value likely including 03levels well above the current 

1-h 03NAAQS of 0.12 ppm. 

3.1.3 Laboratory Animal Studies 

The more recently published reports on the animal toxicology of 0 3were evaluated 

according to their overall relevance to the issues of 0 3toxicology 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, or that corroborated or tended 

to duplicate the content of other studies contained in the Ozone Criteria Document 

(U.S. Environmental Protection Agency, 1986) were eliminated in order to summarize the 

newer pertinent data as briefly as possible. Additional literature has been selected for review 

here that contained information on (1) the effects of multihour and multiday exposures to 0 3 , 

(2) the potential health effects of chronic 03 exposure, and (3) the conceptual and empirical 

linkages between animal and human 0 3toxicology (i.e., extrapolation). Information on a 

less-specific, but nevertheless important, aspect of 0 3toxicity (e.g., "adaptation") is given 

here as well. 

3.1.3.1 Effects of Multihour Exposures 

Three studies on the effects in animals of multihour exposures to 0 3(Table 3-4) have 

been reported (Van Bree et al., 1989; Rombout et al., 1989; Costa et al., 1989). 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 can be modeled mathematically and 

clearly demonstrate the dominance of C in eliciting effects. 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. 

Although further work on this last point is needed, it appears that the C x T approach only 

holds for a given C and cannot be applied in a general fashion. 

3-43 
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Costa et al. (1989) have attempted to address whether the apparent cumulative loss of 

lung function seen with 03exposure 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 exposure, which incorporated ventilation, but only at lower 

concentrations (<0.5 ppm for up to 7 h). At 0.8 ppm, the effect of T on the C'response 

dramatically increased, as was seen in, their matrix studies of C x T relationships a.nd in 

similar studies by Van Bree et al. (1989). Hence, the impact of T is C dependent. It should 

be noted, however, that the apparent cumulative toxicity of 0 3may be endpoint dependent as 

well and that the simpie loss of lung volume, FVC or FEV l , may demonstrate such a 

relationship (linearity) more clearly than more interdependent measures such as DL Co and 

N2washout. 

3.1.3.2 Effects of Multiday Exposures 

An animal model has been developed (Costa et al., 1988) that exhibits the same pattern 

of attenuated response to intermittent short-term 0 3(a phenomenon known as "adaptation") 

as has been described in humans. More specifically, repeated 2-h exposures of rats for up to 

5 days resulted in adaptation or attenuation of the 0 3 -induced functional deficits, with 

sustained but not worsening protein accumulation occurring in the lavage. Howeve.r, 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. This model demonstrates that 

morphological and biochemical changes continue even whiie lung dysfunction attenuates with 

repeated 03exposure, suggesting that the use of lung function tests alone to assess injury can 

result in misinterpretation of risk to health with repeated exposures to 0 3 . Whatever the 

precise mechanisms and attenuation events, however, animal studies have demonstrated that 

chronic exposures cause effects, some of which are irreverisible. 

The protein and PMN response to repeated 12 h nocturnal exposures for up to 3 days as 

an analogue of an 0 3"episode" appeared to be governed by the initial exposure only 

(Van Bree et al., 1989). In other words, the degree of response and recovery time were 

unaltered by additional exposures during the 2- or 3-day period. 

3-45 
3.1.3.3 Effects of Chronic Exposure to Ozone 

Several recent reports on 03effects in laboratory animals have focused on the structural 

alterations of the distal lung associated with prolonged, repeat.ed exposures (see Table 3-5). 

Tn botli the adult and neonate rat (Barry et al. , 1988; Grose et al. , 1989; Huang et al. , 1988; 

Gross and White, 1987) and the monkey (Tyler et al., 1988; Hyde et al., 1989), high 

(;-~ 0.25 ppm) ambient levels of 0 3appear to similarly affect 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 (Crapo et al., 1985; Barry et al., 1985, 1988; 

Sherwin and Richters, 1985). Interstitial inflammation predominates over time, resulting in 

thickened septal areas that do not completely recover during several weeks of postexposure 

clean air (Huang et al., 1988; Barr et al., 1988; Moffatt et al., 1987). These findings are 

largely consistent with the reports of enhanced collagen deposition and reduced turnover with 

very high ambient levels of 0 3(0.57 to 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 low 03concentrations (Filipowicz and McCauley, 1986; 

Wright et al., 1988), unless exposure is intermittent (Tyler et al., 1988). 

A preliminary report from the U. S. EPA's chronic 0 3study (Grose et al. , 1989) 

showed that repeated daily exposure of rats to a daily episodic profile of 0 3(22 h, 0.06-ppm 

background with a 0.25-ppm peak; equivalent to a square wave that averaged 0.19 ppm over 

9 h) for 12 mo resulted in small, but significant, decrements in lung function that were 

consistent with early signs of focal fibrogenesis in the proximal bronchoalveolar junction (see 

Chang et al., 1991). Augmentation of lavagable protein levels and tissue fractions of. 

ascorbate- and glutathione-related enzymes after 12 mo of 0 3exposure were indicative of the 

continued oxidant challenge. Further results of these studies through to 18 mo of exposure 

and with recovery periods will be published. The functional implications of these alterations 

in distal airway architecture have been explored in one higher level 0 3study (0.5 ppm) in 

which airflow mechanics were reversibly altered (Gross and White, 1987). Changes in 

lavagable enzymes in rats (Grose et al., 1989) and lipids in monkeys (Rao et al., 1985a,b) 

after prolonged exposures are consistent with shifting cell populations and/or inflammation, 

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3-51 
but remain nonspecific effects that still need to be linked with progressive injury or defensive 

adjustments to the 03challenge. 

Ozone also 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 03 from both animal and human studies. Hence, though 0 3is 

relatively insoluble in water, the nose appears to provide some degree of scrubbing, and thus, 

provides protection to the deeper lung. 5pecies differences in this capability are an importa.nt 

extrapolation question (see below). 

3.1.3.4 Animal-to-Huwman Extrapolation 

The more recently published studies 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, 

1989) of lower respiratory tract deposition of 0 3has been enhanced with the incorporation of 

both ventilatory parameters and empirically derived anatomical data (see Table 3-6). 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. ainimals. 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). Although 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 increase confidence in the 

model (Gerrity and Wiester, 1987). 

Both human and animal uptake studies of 0 3have been conducted (see Tables 3-1 and 

3-6). Although humans (Gerrity et al., 1988) appear to retain a somewhat greater fraction of 

the inhaled 03than do rodents (Wiester et al., 1988), the biological significa.nce of this 

difference is uncertain at this time, especially considering the slight differences in technique. 

Santrock et al. (1989) have shown that with continued exposure, products of 0 3 , as indicated 

by an oxygen-18 (180) label, accumulate in -the lungs of mice with continued exposure. The 

difference in total uptake between humans and laboratory rodents may result in part from 

differences in nasopharyngeal removal of 0 3(40 % in humans, 17 % in rats; as reported by , 

3-52 
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Hatch et al., 1989), 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 antioxidants 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, especially considering that five anim.al species tested 

for 03 toxicity in concentration-response studies using BAL protein did not show 

corresponding variations in their susceptibilities (Hatch et al., 1986). Thus, target tissue 

dosimetry data, such as that being pursued with i80 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, 1989). Further work is still n..eded,• 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., 1989). 

3.2 SUMMARY AND CONCLUSIONS: HEALTH EFFECTS I1ATA 

Concisely summarized below are the key findings and conclusions that emerge from the 

above review of the most pertinent, key 0 3health effects studies published in the 1986 to 

early 1989 period after completion of the 1986 U.S. EPA Ozone Criteria Document. 

The newer studies reviewed from the 1986-1989 period provide further inforrnation 

related to evaluation of several key issues pertinent to decision making regarding potential 

revision of the primary 0 3NAAQS. Such issues include: (1) clarification of exposure 

dynamics (i.e., characterization of effective exposure patterns-concentrations, durations, etc.) 

determining the induction of acute effects (pulmonary function decrements, respiratory 

symptoms, lung inflammation, etc.) associated with short-term 0 3exposures; (2) evaluation 

of potential increased (or decreased) susceptibility of various population groups earlier 

hypothesized as possibly being at differential risk for 0 3-induced health effects; (3) evaluation 

of the potential for induction of chronic lung damage/disease by repeated short-term and/or ` 

more chronic 03exposures; and (4) additional clarification of 0 3dosimetry aspects of 

3-56 
importance in better understanding observed human exposure effects and to enhance 

capabilities to carry out both qualitative and quantitative animal-to-human extr.apolations. 

3.2.1 Exposure Dynamics for Short-Term Ozone Exposure Effects 

Newer data from 1- and 2-h controlled human exposure studies (Avol et al., 1987; Linn 

et al., 1986) add to earlier existing concentration-response data indicating that lung function 

decrements occur in children and young' adults exposed for 1 to 2 h to low 0 3concentrations 

ranging from 0.12 to 0.16 ppm while performing moderate to heavy exercise. Explanations 

for variations across studies in reported lowest-observed-effects-levels among individuals and 

among cohorts include: subject characteristics, exposure histories of subjects, exercise levels, 

and possible but presently unidentified differeinces in actual controlled exposure conditions. 

Data from two other newer studies (Gong et al., 1986; Schelegle and Adams, 1986) 

also substantiate earlier findings that statistically significant reductions in maximal exercise 

performance may occur in well-conditioned athletes after performing conxinuous heavy 

exercise (VE> 80 L/min) for 1 h at 0 3concentrations >_0.18 ppm, but not at 0.12 ppm. 

Data from a third study (Linder et al. , 1988) suggest that small decrements in maximai 

exercise performance may occur at 0 3concentrations < 0.18 ppm, but liinitations 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. 

In addition, newly emerging controlled human exposure studies of prolonged exposure 

(for up to 6.6 h) to low 0 3concentrations, ranging from 0.08 to 0.12 ppm report 

progressively larger pulmonary function decrements and increased respiratory symptoms with 

increasing duration of exposure at moderate exercise levels ( VE= 40 L/min) (Folinsbee 

et al., 1988; Horstman et al., 1988, 1989). The effects are similar in magnitude to those 

previousiy reported for healthy subjects performing heavy exercise (VE> 60 L/min) in high 

ozone concentrations (>0.2 ppm) for shorter durations, (:Z-2 h). 

In addition to the above, new data also demonstrate increased lung inflammatory and 

biochemical changes from exposures to moderately high levels (0.40 ppm) of 0 3for 2 h with 

intermittent exercise (V E = 70 L/min), as determined from BAL 18-h post-0 3 -exposure 

3-57 
(Koren et al., 1989a,b; 1988a,b). Cells and enzymes capable of causing damage to 

pulmonary tissues, along with proteins involved in fibrotic and fibrinolytic processes, were 

increased at 18-h postexposure. Also, evidence of increased epithelial permeability from the 

air to blood compartments (as determine,d by clearance of technetium-labeled DPTA) was 

observed (Kehri et al., 1987). Koren et al. (1989a) further reported elevated PMNs, also as 

determined by BAL, in subjects exposed for 6.6 h to 0.1 ppm 0 3 . 

Three newer studies on the effects in laboratory animals of multihour 0 3exposures 

provide information on relationships between concentration (C) and duration (T, time) of 

exposure. Rombout et al. (1989), Van Bree et al. (1989), and Costa et al. (1988) report that 

C dominates T in eliciting 03-induced changes in lavagable protein and antioxidant enzyme 

levels. Preliminary modeling efforts describing these data suggest that C x T interaction 

(synergism) occurs at decreased C and increased T; however, C x T 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 oxida.nt toxicity because nocturnal exposures cause greater 

responses than do diurnal exposures, possibly due to dosimetric differences because rats 

exercise more at night. These results suggest that the primary determinants of acute 0 3lung 

toxicity may, therefore, be exposure concentration and time of day of exposure, followed by 

the duration of exposure. 

Also, certain other newer information suggests that interpretation of the results of 

controlled human 03exposures should take into account whether frequent ambient exposure 

was a possibility during the period of study (Avol et al., 1988; Hackney and Linn, 1989; . 

1`Iackney et al., 1989; Linn et al., 1988). This information also suggests that further work is 

still needed to resolve the implications of attenuation of pulmonary function responses to 

03 . Subjects grouped according to their responses in the early spring to 0.18 ppm 0 3for 

2 h with intermittent exercise were tested the following fall, winter, and again the next 

spring. Although "nonresponders" showed little seasonal variation in their response to 

03 , "responders" showed attenuated responses in the fall, persistence of attenuation into the 

winter, and a return to their initial lung function responses to 03 by the following spring. 

Many of the responders were reactive to methacholine and had histories of respiratory 

allergies and/or symptomatic complaints when previously exposed to smog. 

3-58 
Newer field a.nd epidemiological studies have employed numerous refinements over 

some of the older studies, in the form of (a) better estimates of exposure, not just to 0 3but 

also to other pollutants and other environmental variables that can confound or otherwise 

influence the outcome (e.g., Bates and Sizto, 1987; Spektor et al., 1988a;b; Raizenne et al., 

1987); (b) use of serial measurements of pulmonary function for determining correlations 

with pollutants and other environmental variables (e.g., Raizenne et al., 1987, 1989; Spektor 

et al., 1988a,b); and (c) better biomedical characterization of cohorts (e.g., Raizenne et al., 

1987, 1989; Gong, 1987). Despite their refinements, however, newer field a.nd 

epidemiologic studies have produced mixed results regarding the possible role of 0 3versus 

the roles of other agents or factors in eliciting the functional decrements and/or rates of 

respiratory symptoms or respiratory disease observed. Although functional decrements and 

respiratory symptoms have been shown in a number of studies to be statistically associated 

with 03 , other studies have shown them to be wholly attributable to particles (e.g., Dockery 

et al., 1989), partially attributable to particles (e.g., Kinney, 1986), or partially attributable 

to other environmental factors such as ambient temperature or humidity (e.g., Spektor et al., 

1988a) or even aeroallergens (e.g., Dockery et al., 1989; Gong, 1987). 

Data reported from some of the newer field and epidemiologic studies (e. g. , Raizenne 

et al., 1987, 1989; Spektor et al., 1988a,b; Kinney et al., 1988) show pulmonary function 

decrements that are as large or larger than those observed in human controlled (chamber) 

studies. Investigators have variously interpreted these larger decrements as likely being due 

to: (a) cumulative effects of 0 3occurring as the result of multihour exposures; 

(b) interactive effects with other pollutants (additive or synergistic effects); (c) interactive or 

possibly independent effects of other environmental factors (e.g., temperature); (d) possible 

misspecification of true exposures, either because of inadequate knowledge of dosimetry or 

other types.of inadequacies in exposure characterization; and/or (e) possible persistence of 

effects from one day to the next. 

Although permitting easier comparison of epidemiologic findings with chamber-study 

data, the method of reporting raises several questions that need to be further evaluated. For 

example, data on functional decrernents have been reported as —mL/ppb 0 3for measures 

such as FEV 1 oand FVC and as —mL/sec/ppb for measures such as PEFR and MMEF. 

Expression of data in this form assumes that (a) 0 3 -induced changes in respiratory function 

3-59 
are linear across all concentrations encountered in these studies (from zero up through 

episodic levels); and (b) the relationships among C, T, and VEdo not change with variations 

in these respective components of exposure. These assumptions are open to question, 

especially considering results from newer animal C x T studies. For example, the 

relationships between respiratory function changes and the respective -components of exposure 

—C, T, and VE—have not been tested at concentrations <0.08 ppm in char.nber studies; and 

data obtained in chamber studies at the lowest concentration used (0.08 pprn) have not been 

modeled to determine whether changes in the influence of respective components are 

monotonic across ranges of C, T, or V E. Furthermore, questions of nonlinearities in the 

respective effects of C, T, and VE on 03 -induced pulmonary function changes are far from 

resolved. Also, Kinney et al. (1988), transformed data from controlled (chamber) studies 

modeled by Hazucha• (Hazucha, 1987; U.S. Environmental Protection Agency, 1986) and 

compared them with data from five epidemiologic studies. The transformation assumed the 

applicability 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 

VE. Mean concentrations in the five epidemiologic studies were lower than the lowest 

concentration used in the controlled studies modeled. 

As for respiratory symptoms, the newer field and epidemiologic studies have reported 

lack of association of various respiratoiy symptoms with 0 3more often than they have 

reported demonstration of such an association with the typically low 0 3levels studied. 

Studies reporting no significant increases in symptoms following short (1-h to multihour) 

daily exposures (over multiple days to multiple months) to ambient air containing 0 3include: 

(a) studies of children attending day or residential camps (Raizenne et al. , 1987, 1989; 

Spektor et al., 1988a), (b) at least two panel studies (Dockery et al., 1989; Vedal et al., 

1987), and (c) a study of adults exercising outdoors nearly every day (Spektor et al., 1988b). 

Another study (Schwartz et al., 1988), reanalyzing data from the Hammer et al. (1974) panel 

study of nurses in Los Angeles and using currently more widely accepted statistical 

approaches, did show that cough was associated with total oxidants, but only at relatively 

high levels (where 03concentrations were likely well above 0.12 ppm). 

3-60 
3.2.2 Evaluation of Differential Susceptability of Potential Special Risk 

Groups 

Newer data published in the 1986-1989 period provides further data usefui in evaluating 

possible differential sensitivity in two of several subpopulation groups of interest: (1) the 

elderly and (2) asthmatics. With regard to the first group, in controll.ed human exposure 

studies, older subjects (>_50 years old) appear to have smaller changes in lung function than 

younger subjects when exposed to similar 0 3concentrations (Bedi et al., 1988; Bedi and 

Horvath, 1987; Drechsler-Parks et al., 1987, 1989; Reisenauer et al., 1988). There were no 

significant differences between the responses of inen and women to 03exposure for FEV 1 

and FVC, although women had a significant increase in total respiratory resistance 

(Reisenauer et al., 1988). Because women had slightly lower mean exercise VEduring the 

studies, the data suggest that women may be somewhat more responsive to 0 3than men 

(Drechsler-Parks et al., 1987; Reisenauer et al., 1988). The responses to 0 3may be less 

reproducible, however, in older than in younger adults (Bedi et al., 1988). These results 

suggest a possible dropoff in responsiveness to 0 3-induced pulmonary function changes 

sometime in late middle-age. 

As for asthmatics, in other new studies of adults with and without asthma (Kreit et al., 

1989; Eschenbacher et al., 1989), both groups experienced similar responses to 0.4-ppm 

03exposure, as indicated by decrements in standard spirometric pulmonary function tests and 

airway responsiveness to methacholine. Specific airway resistance was not increased in 

nonasthmatics, but in asthmatics nearly twice the increase in SR aWwas seen after exercise in 

03versus air exposures. No symptom differences were observed between adult asthmatics 

and nonasthmatics. Preexposure challenge with methacholine may have confounded the 

resuits, however. Responses were also similar for adolescent asthmatics and nonasthmatics 

exposed to 0.12 and 0.18 ppm 0 3(Koenig et al., 1987, 1988), although a small but 

significant increase in FEF50%was observed in asthmatics after 0.12 ppm 0 3exposure. In 

the adult nonasthmatics studied by Eschenbacher et al. (1989), indomethacin pretreatment 

blocked the restrictive but not the airway reactivity component of the effects of 0 3 ; 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 0 3as a comparable group of nonallergic subjects. The only 

'il 
difference was a significant increase in airway resistance in the allergic subjects. The newer 

data on allergic and asthmatic subjects suggest that both of these groups have a greater 

increase in airway resistance after 0 3exposure than do healthy subjects. The apparent order 

of airway responsiveness to 0 3from these studies is normal < allergic < asthmatic subjects. 

Further research will be required, however, before this hypothesis can be substantiated. 

Results from a few of the newer epidemiology studies are also suggestive of possible 

increases in asthma or allergic responses among some individuals. For exainple, Dockery 

et al. reported a positive association of annual 0 3exposures to increases in asthma and hay 

fever symptoms in schoolchildren, but not with other respiratory symptoms or pulmonary 

function decrements. Also, in a panel study more specifically on asthmatics, Gong (1987) 

reported that, although respiratory symptoms occurred during the study, they did not correlate 

signifiicantly with 03 ; and no worsening of syinptoms attributable to 03 occurred in overall 

group statistical analyses. However, other multiple regression analyses of responses of those 

asthmatics in the top quartile for respiratory measures did show relationships between the 

respiratory measures and 0 3 , but these associations showed no clear concentration-response 

pattern (Gong, 1987). 

3.2.3 Ozone Impacts on Lung Structure/Chronic Disease Processes 

Several studies, by Koren et al. (1988a,b; 1989a,b) and Kehrl et al. (1987), were noted 

earlier as showing increased lung inflammatory responses and other biochernical changes 

capable of causing damage to pulmonary tissue, as well as increased lung epithelial 

permeability, with 2-h exposures of humans to 0.4 ppm 03and elevated PMI'1s in BAL fluids 

following 6.6-h exposure to low 03levels (0.1 ppm). These results increase concern 

regarding possible induction of chronic lung damage by 0 3exposures and lead to questions 

about effective exposure dynamics possibly related to such effects. 

Costa et al. (1988) have demonstrated that laboratory animals exhibit a similar pattern 

of attenuated pulmonary function changes in response to repeated short-term 0 3exposure as 

previously described in humans. Both morphological and biochemical changes, however, 

occur wliile lung dysfunction attenuates with repeated 0 3exposure. These results add to 

coneern that the attenuation phenoinenon for short-term pulmonary functioii changes may not 

be benefieial, but rather may increase the potential for more serious chronic lung damage. 

3-62 
They also suggest that the use of lung function tests alone to assess 03-induced lung injury 

may result in misinterpretation of data concerning health risks associated with multiday 

03exposures. More research is needed, therefore, to improve our knowledge of 

relationships between acute and chronic lung injury. 

Other new studies in monkeys and rodents provide further support for earlier findings 

that prolonged, repeated exposure to high concentrations of 0 3(>0.4 ppm) lead to the 

development of peribronchiolar inflammation (Barr et al., 1988; Moffatt et al., 1987), 

increased lung collagen content (Reiser et al. , 1987; Pickrell et al. , 1987; Hacker et al. , 

1986), and lung function changes (Gross and White, 1986, 1987). Even at lower 

03concentrations (0.12 to 0.30 pnm), 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 et al., 1988; Crapo et al., 

1985; Barry et al., 1985, 1988; Sherwin and Richters, 1985), but without increased lung 

collagen content in rats (Wright et al., 1988; Filipowicz and McCauley, 1986). 

In a chronic exposure study (0.25 ppm, 8 h/day, 18 mo), one group of monkeys was 

exposed to 03for each day of the 18 mo, whereas another group was exposed to 0 3every 

other month, with the intervening month being an air exposure (Tyler et al., 1988). Thus, 

on a C x T basis, the intermittent group received half the amount of 03 exposure. Both 

groups of monkeys had morphometric changes, such as respiratory bronchiolitis, but only the 

intermittent groups had an increase in total lung collagen and pulmonary function changes. 

This suggests that under these experimental conditions, intermittent exposure could enhance 

the potential for the development of fibrogenic processes and indicates that to understand the 

health effects of 0 3 , it is critical to better understand the effects ambient exposure patterns. 

Preliminary information (Grose et al., 1989) from an exposure that mimics an urban 

03pattern (0.19 ppm average concentration of 0 3over 9 h) of rats for 12 mo indicates that 

significant decrements in lung function also occur at these iower 0 3concentrations that are 

consistent with early signs of focal fibrogenesis in the centriacinar region of the lung. 

Increased lavagable lipids in monkeys (Rao et al., 1985a,b) found after prolonged exposure to 

ambient levels of 0 3(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 h/day for 6 or 90 days) also cause injury and cellular changes in 

3-63 
transitional and respiratory epithelium of the nose of nonhuman primates (Harkema et al., 

1987a,b; Hyde et al., 1989). 

3.2.4 Ozone Dosimetry Aspects 

Newer studies related to the dosimetry of 0 3show that differences in mode of breathing 

do not produce appreciable differences in fractional uptake of 0 3in the respective regions of 

the human respiratory tract. Increased frequency of breathing results in a decreased fractional 

removal of 03in both the URT and the LRT, possibly as the result of decreased residence 

time in the airways and increased flow rate. The lowest fractional removal of 0 3in 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 et al., 1988). Ozone-induced changes in tidal volume during 60-min, 

continuous-exercise (VE= 40 L/min) exposures to 0.4 ppm resulted in a slight reduction in 

total 03uptake (4 %) and a larger reduction in LRT 0 3uptake (9 %). Thus, the typical 

03-induced reduction in tidal volume may partially protect the lower airways, with possible 

loss of that protection with recovery of normal tidal volume that occurs during multiday 

exposure (Gerrity and McDonnell, 1989). Increased flow rates appear to reduce 

nasopharyngeal uptake (Gerrity, 1987). Additional modeling is need, howe•ver, to determine 

the effects of heavy exercise on regional dosimetry, especially on 0 3uptake in the LRT. 

Additional data are still needed in other areas important to animal-to-human extrapolation, 

namely, relative species sensitivities. 

Iviathematical dosimetry models indicate preferential deposition of 0 3in the 

bronchoalveolar junction of several species of laboratory animals and in humans that is 

consistent with laboratory animal data on the site of the 0 3morphological lesion (Miller and 

Overton, 1989; Miller et al., 1987a,b; Overton et al., 1987). Humans appear to retain a 

greater fraction (95%) of inhaled 0 3than do rats (50%), but tissue dose rates/surface 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]0 3(Hatch et al., 1989; Santrock et al., 1989; Aissa and 

Hatch, 1988; Hatch and Aissa, 1987) ai -e needed, along with species sensitivity data (Bryan 

and Jenlcinson, 1987; Hatch et al., 1986; Slade et al., 1985) to better refine this issue. 

3-64 
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