Acute effects of 0.12 ppm ozone or 0.12 ppm nitrogen dioxide on pulmonary function in healthy and asthmatic adolescents

Adolescent asthmatic subjects have been shown to be much more sensitive than healthy adolescents to the inhaled effects of sulfur dioxide. To test whether similar adolescent asthmatics are more sensitive to other common ambient air pollutants, 10 healthy and 10 asthmatic adolescent subjects were exposed for 60 min to filtered air, 0.12 ppm ozone (O3), and 0.12 ppm nitrogen dioxide (NO2) on separate days at rest. The following pulmonary functional values were measured before, at 30 min, and after 60 min of exposure: peak flow, total pulmonary resistance (RT), thoracic gas volume at functional residual capacity (FRC), maximal flow at 50 and 75% of expired vital capacity (Vmax50 and Vmax75), and forced expiratory volume in one second (FEV1). Following 60 min of exposure at rest to low concentrations of O3 or NO2, there were no consistent significant functional changes in either healthy or asthmatic adolescent subjects. There also were no measurable differences between the 2 groups.     

Reproducibility of individual responses to ozone exposure

Because large intersubject differences in the magnitudes of response to a single ozone (O3) exposure have been observed, we undertook to determine if this variability were due to differences in intrinsic responsiveness to O3 or to other factors. Thirty-two subjects were exposed to 1 of 5 O3 concentrations (0.12, 0.18, 0.24, 0.30, or 0.40 ppm), and each underwent one or more repeat exposures separated by from 3 wk to 14 months. Magnitudes of change for pulmonary function variables, respiratory rate and tidal volume, and for reported symptoms were compared for the repeated exposures. Changes induced in forced expiratory spirometric measurements were highly reproducible for as long as 10 months and for all tested O3 concentrations of 0.18 ppm or greater. This high degree of reproducibility indicates that the magnitude of response to a single exposure is a precise estimate of that subject's intrinsic O3 responsiveness. We conclude that the previously observed intersubject variability in magnitude of O3-induced effects is the result of large differences in intrinsic responsiveness to O3.     

Effect of 2 ppm ozone exposure on rat lung lipid fatty acids

Based on in vitro studies, the initial damage to lung cells by ozone exposure is believed to result in part from the breakdown of lipid polyunsaturated fatty acids to aldehydes, ozonides, and peroxides. The present study measured lipid breakdown products in lungs isolated from rats pretreated with [1-14C]acetate 12 h before exposure for 4 h to either air or 2 ppm ozone. Lipid fatty acid breakdown was indicated by a 112% increase in thiobarbituric acid-reactive substances on ozone exposure and by changes in chemical and radioactive measurements of mono- and dicarboxylic acids formed by treatment of lipid fractions with hydrogen peroxide. Ozone exposure resulted in a 63% increase in recovery of short-chain fatty acids accounted for by increased recoveries of malonic acid by 37%, hexanoic acid by 47%, nonanoic acid by 118%, and azelaic acid by 107%. Recovery of glutaric acid was enhanced 15-fold by ozone exposure. Although decreases in tissue arachidonic acid could not be detected, oleic acid was significantly decreased by 36%. Recovery of radiolabel as short-chain fatty acids was increased by 65% on ozone exposure and was mainly accounted for by enhanced labeling of nonanoic and glutaric acid fractions. The failure to observe significant increases in 14C recovery in the other fractions suggested ozone-induced breakdown of unlabeled fatty acids. These results demonstrate the cleavage of unsaturated fatty acid double bonds following in vivo exposure of lungs to ozone. Breakdown of arachidonic and oleic acids was specifically identified by increased recoveries of glutaric and nonanoic acids, respectively.     

Suppression and recovery of the alveolar macrophage phagocytic system during continuous exposure to 0.5 ppm ozone

Short-term exposures to ozone (O3) are known to impair pulmonary antibacterial defenses and alveolar macrophage (AM) phagocytosis in a dose-related manner. To determine the effect of prolonged O3 exposure, Swiss mice were exposed continuously to 0.5 ppm O3. At 1, 3, 7, and 14 days, intrapulmonary killing was assessed by inhalation challenge with Staphylococcus aureus or Proteus mirabilis and by comparing the number of viable bacteria remaining in the lungs at 4 h between O3-exposed and control animals. To evaluate the effects of O3 on the functional capacity of the AMs, Fc-receptor mediated phagocytosis was assessed. Ozone exposure impaired the intrapulmonary killing of S. aureus at 1 and 3 days; however, with prolonged exposure, the bactericidal capacity of the lungs returned to normal. This trend of an initial suppression followed by recovery was reflected in the phagocytic capacity of the AMs. In contrast to S. aureus, when P. mirabilis was used as the challenge organism, O3 exposure had no suppressive effect on pulmonary bactericidal activity, which correlated with an increase in the phagocytic cell population in the lungs. Morphologic examination of the lavaged macrophages showed that after 1 day of O3 exposure, the AMs were more foamy, and contained significantly more vacuoles. There was also a significant increase in binucleated cells at 3 days. These studies demonstrate that continuous exposure to O3 modulates AM-dependent lung defenses and points to the importance of the challenge organism and exposure protocol in establishing the adverse effect of O3.     

Acute response to 3.0 ppm formaldehyde in exercising healthy nonsmokers and asthmatics

Formaldehyde is an ubiquitous industrial and indoor air pollutant to which millions are daily exposed. Because of the paucity of scientific data concerning the inhalation toxicity of this compound in humans, we determined the symptoms and alterations in pulmonary function resulting from inhalation for 1 h of 3 parts per million formaldehyde in a controlled environmental chamber. The protocol consisted of randomized exposure of each subject to clean air or 3.0 ppm HCHO on 2 separate days. Twenty-two healthy normal subjects engaged in intermittent heavy exercise (VE = 65 L/min) and 16 asthmatic subjects performed intermittent moderate exercise (VE = 37 L/min). Symptoms and pulmonary function were assessed during the time course of exposure; nonspecific airway reactivity was assessed after exposure. Both groups exhibited similar, significant (p less than 0.01) increases in perceived odor, nose/throat irritation, and eye irritation throughout the exposure. The normal group had the following statistically significant (p less than 0.02) lower pulmonary functions after 55 min of exposure to formaldehyde as compared to clean air: 3.8% in FEV1, 2.6% in FVC, and 2.8% in FEV3. The asthmatic group showed no statistically significant decrements in pulmonary function. Five of 38 subjects studied had decrements in FEV1 greater than 10%. In conclusion, acute exposure to 3 ppm HCHO produced: consistent irritant symptoms in both normal and asthmatic subjects, small decreases in pulmonary function in normal subjects engaging in heavy exercise, and clinically significant responses (defined here as decrements in FEU1 greater than 10) in 13% of the study population.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary function responses of older men and women to ozone exposure

The pulmonary function of 8 men and 8 women (51 to 76 years of age), all nonsmokers, was measured before and after 2-h exposures to filtered air (FA) and 0.45 ppm ozone (O3). The subjects alternated 20-min periods of rest and 20-min periods of cycle ergometer exercise at a workload predetermined to elicit a ventilatory minute ventilation (VE) of approximately 25 L/min (BTPS). Functional residual capacity (FRC) was determined pre- and post-exposure. Forced vital capacity (FVC) was determined before and after exposure, and 5 min after each exercise period. Ventilatory minute volume (VE) was measured during the last 2 min of each exercise period, and heart rate was monitored throughout each exposure. The pulmonary function data were evaluated as the percentage change from pre- to post-exposure to partially remove the effect of differences between men and women in absolute lung volume. There were no statistically significant (p greater than 0.05) differences between the responses of men and women to FA or O3 exposure. There were no significant (p greater than 0.05) changes in any variable consequent to FA exposure. Exposure to O3 induced significant (p less than 0.01) decrements in FVC, FEV1.0, and FEV3.0 at post-exposure compared to pre-exposure. Ozone exposure induced no significant (p greater than 0.05) effect on FEF25-75% or FEF75%. Men had a significantly (p less than 0.05) higher mean exercise VE than women (27.9 +/- 0.29 L vs. 25.4 +/- 0.8 L; mean +/- SD). Since the men and women had similar decrements in pulmonary function, even though the women inhaled less O3, the data suggest that women may be somewhat more responsive to O3 than men. We also compared the responses of our older subjects with those of young men and women that we studied with the same protocol, and with published results of other investigators who have studied young men and women. This comparison suggests that older individuals may be less responsive to O3 than young individuals.     

The effects of sequential exposure to acidic fog and ozone on pulmonary function in exercising subjects.

In Southern California coastal regions, morning fog is often acidified by the presence of nitric acid (HNO3). Peak exposure to ozone (O3) usually occurs in the afternoon and evening, after the fog has dissipated. To determine whether fog containing HNO3 might enhance pulmonary responses to O3, we studied a group of healthy, athletic subjects selected for lung function sensitivity to O3. On 3 separate days, the subjects exercised for 2 h in atmospheres containing HNO3 fog (0.5 mg/ml), H2O fog, or clean, filtered air. After a 1-h break, they exercised for an additional 3 h in an atmosphere containing 0.20 ppm O3. Surprisingly, the mean O3-induced decrements in FEV1 and FVC were smaller after exercise in each fog-containing atmosphere than they were after exercise in clean, filtered air. The mean (+/- SEM) O3-induced decrements in FEV1 were 26.4 +/- 5.3% after air, 17.1 +/- 3.7% after H2O fog, and 18.0 +/- 4.3% after HNO3 fog, and in FVC they were 19.9 +/- 4.7% after air, 13.6 +/- 2.8% after H2O fog, and 13.6 +/- 4.2% after HNO3 fog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Respiratory symptoms in children and exposure to pesticides.

In Lebanon, childhood asthma is an important disease and pesticides are commonly used. The objective of this study was to evaluate whether exposure to pesticides has chronic effects on the respiratory health of Lebanese children. A cross-sectional study was performed on children from a randomly selected sample of Lebanese public schools. Exposure to pesticides was evaluated by a standardised questionnaire and a residential exposure score, and respiratory symptoms were assessed by using the American Thoracic Society standardised questionnaire. A chronic respiratory disease was reported in 407 (12.4%) out of 3,291 children. The baseline difference in mean age was small but statistically significant. Any exposure to pesticides, including residential, para-occupational and domestic, was associated with respiratory disease and chronic respiratory symptoms (chronic phlegm, chronic wheezing, ever wheezing), except for chronic cough. Exposure to pesticides was associated with chronic respiratory symptoms and disease among Lebanese children.     

Effect of ozone exposure on airway responses to inhaled allergen in asthmatic subjects

BACKGROUND: Controlled human exposure studies have produced conflicting results regarding the effect of ozone on the early bronchoconstrictor response to inhaled allergen in specifically sensitized asthmatic subjects. Spirometric parameters do not necessarily reflect the airway inflammatory effects of inhaled ozone or allergen. OBJECTIVE: This study was designed to investigate whether exposure to ozone enhances the late airway inflammatory response, as well as the early bronchoconstrictor response, to inhaled house dust mite allergen in sensitized asthmatic subjects. DESIGN: Randomized, counter-balanced, cross-over study. SETTING: Human exposure laboratory. METHODS: Fourteen subjects were exposed to 0.2 ppm O(3) or filtered air, on separate days, for 1 h during exercise. After each exposure, the subjects were challenged with doubling doses of Dermatophagoides farinae (DF) allergen (provocative concentration of DF causing a 15% decrease in FEV(1) [PC(15)]). At 6 h after allergen challenge, bronchoscopy with BAL, proximal airway lavage (PAL), and endobronchial biopsy were performed. The second exposure/allergen challenge/bronchoscopy sequence was performed at least 4 weeks after the first sequence. RESULTS: No significant difference in cellular or biochemical markers of the late inflammatory response after allergen was found between the ozone and air exposures (although a trend toward increased neutrophils was noted after ozone exposure in the PAL fluid, p = 0.06). For the group as a whole, no significant difference in PC(15) was demonstrated after ozone exposure compared to air exposure. However, subjects with the greatest ozone-induced decrements in FEV(1) tended to have lower PC(15) values after ozone exposure. CONCLUSION: Exposure to a relatively low-level concentration of ozone does not enhance the late inflammatory or early bronchoconstrictor response to inhaled antigen in most allergic asthmatic subjects. Our results do suggest, however, that a subgroup of asthmatics may acquire increased sensitivity to aeroallergens after exposure to ozone.     

In vivo exposure to ozone causes increased in vitro responses of small airways

We examined the effects of in vivo exposure to 3 ppm ozone on in vitro reactivity of large and small airways from dogs. No effects in large airways were detected. However, small airways exposed to O3 had larger responses to receptor-mediated stimuli and similar responses to KCl plus phorbol ester. These results suggest that small airways are more vulnerable to O3 inhalation than are large airways and that receptor-mediated pathways reflect that sensitivity. Another possible explanation is that O3 exposure prevents the epithelium from playing its normal dampening role in responses to contractile agonists.     

Assessment of personal exposure to ozone in asthmatic children residing in Mexico City

OBJECTIVE: A study was conducted to evaluate personal ozone exposure (O3p) among asthmatic children residing in Mexico City. MATERIAL AND METHODS: A total of 158 children were recruited from December 1998 to April 2000. On average, three O3p measurements were obtained per child using passive badges. Time-activity patterns were recorded in a diary. Daily ambient ozone measurements (O3a) were obtained from the fixed station, according to children's residence. Levels of O3a and ozone, weighted by time spent in different micro-environments (O3w), were used as independent variables in order to model O3p concentrations using a mixed-effects model. RESULTS: Mean O3p was 7.8 ppb. The main variables in the model were: time spent indoors, distance between residence and fixed station, follow-up group, and two interaction terms (overall R(2)=0.50, p<0.05). CONCLUSIONS: The O3w concentrations can be used as a proxy for O3p, taking into account time-activity patterns and the place of residence of asthmatic Mexican children.     

Differential proinflammatory cytokine responses of the lung to ozone and lipopolysaccharide exposure during postnatal development

Age appears to be a critical variable in the ability of the lung to cope with external stress. Alterations in cellular responses associated with environmental toxicants are likely to modify the developmental processes. This would suggest that the timing and interaction between exposure and developmental events appears to play an important role as susceptible targets for environmental perturbation. C57BL/6 mice ages 2, 4, 7, 10, 14, 28, and 56 days were exposed to 2.5 PPM ozone for 4 hours or to a 10-minute inhalation of lipopolysaccharide (LPS) with an estimated deposited dose of 26 EU and examined 2 hours post exposure. Abundance of proinflammatory cytokine and chemokine mRNA were measured by RNase protection assay. After ozone exposure interleukin (IL)-6 was not detected in 2-, 4-, and 7-day-old mice; however, increases of 18- to 20-fold were measured in 10-, 14-, 28-, and 56-day-old mice. Macrophage inhibitory protein (MIP)-2 and cytokine-induced neutrophil chenocettractant (KC) were elevated slightly, with no differences between 2- and 56-day-old mice. After LPS exposure, IL-6 was not detected in 2- and 4-day-old mice; however, 8- to 10-fold increases were measured in 7-, 14-, and 28-day-old mice and approximately 20-fold in 56-day-old mice. IL-1beta was elevated approximately 4-fold at 2 and 4 days of age but was elevated 25- to 30-fold in 7-, 14-, 28-, and 56-day-old mice. MIP-2 and KC mRNA abundance was elevated 25- to 30-fold, with no differences between 2- and 56-day-old mice. These results demonstrate that critical time points exist during lung development to inhaled environmental pollutants and that differences exist in the maturation of inflammatory and epithelial defense mechanisms.     

Responses of subjects with chronic obstructive pulmonary disease after exposures to 0.3 ppm ozone

We previously reported (American Review of Respiratory Disease 1982; 125:664-669) that the respiratory mechanics of intermittently exercising persons with chronic obstructive pulmonary disease (COPD) were unaffected by a 2-h exposure to 0.2 ppm ozone. Employing a single-blind, cross-over design protocol, 13 white men with nonreversible COPD (9 current smokers; mean FEV1/FVC, 56%) were randomly exposed on 2 consecutive days for 2 h to air and 0.3 ppm ozone. During exposures, subjects exercised (minute ventilation, 26.4 +/- 3.0 L/min) for 7.5 min every 30 min; ventilation and gas exchange measured during exercise showed no difference between exposure days. Pulmonary function tests (spirometry, body plethysmography) obtained before and after exposures were unchanged on the air day. On the ozone day the mean airway resistance and specific airway resistance showed the largest (25 and 22%) changes (p = 0.086 and 0.058, respectively). Arterial oxygen saturation (SaO2) obtained in 8 subjects during the last exercise interval showed a mean decrement of 0.95% on the ozone exposure day; this change did not attain significance (p = 0.074). Nevertheless, arterial oxygen desaturation may be a true consequence of low-level ozone exposure in this compromised patient group. As normal subjects undergoing exposures to ozone with slightly higher exercise intensities show a threshold for changes in their respiratory mechanics at approximately 0.3 ppm, our data indicate that persons with COPD are not unduly sensitive to the effects of low-level ozone exposure.     

Respiratory bronchiolitis following long-term ozone exposure in bonnet monkeys: a morphometric study

To quantitate the response of respiratory bronchiolar (RB) epithelium and peribronchiolar connective tissue (PCT) to chronic exposure to high ambient levels of ozone, two groups of 8 adult male bonnet monkeys each were subjected 8 h daily for one year to 0.64 ppm (UV standard) ozone or filtered air, respectively. Blocks of tissue selected throughout the lung and from first generation RBs following airway microdissection had the following significant exposure-related changes: 57% greater volume of RB in the lung, 27% smaller diameter of RB lumen, 179% thicker media and intima of peribronchiolar arterioles, 61% thicker RB epithelium, and 77% thicker PCT. The increase in thickness of the RB wall resulted primarily from an 84% increase in PCT, with the remainder from the epithelium. Estimates of cellular numerical density showed an 81% increase in cuboidal bronchiolar cells and an 87% decrease in type 1 pneumocytes in the exposed group. Cell volumes from serial section reconstruction showed significantly larger cuboidal bronchiolar (79%), ciliated (117%), and type 2 (66%) cells over controls. Significant PCT changes included more amorphous extracellular matrix (288%), neutrophils (1523%), and lymphocytes/plasma cells (307%). The number of fibroblasts and the volume of extracellular fibers were larger than control values by 44% and 31% in the exposed group, but these changes were not statistically significant. Centriacinar changes due to exposure to long-term, high ambient ozone in bonnet monkeys results in narrowing of respiratory bronchioles primarily by peribronchiolar inflammation (inflammatory cells, fibers, amorphous matrix) and secondarily through hyperplasia of cuboidal bronchiolar cells.     

Airway response to ultra short-term exposure to ozone

To determine whether acute short-term exposure to oxidant pollutants can cause changes in respiratory mechanics, we gave 0.5 ppm ozone for 5 min to 7 baboons. We measured pulmonary resistance (RL) and obtained dose response curves to methacholine before and after the exposures. This brief insult increased resistance (control RL = 1.53 +/- 0.21 cm H2O.L-1 s; post-ozone RL = 3.53 +/- 0.54 cm H2O.L-1 s). On a second occasion, 6 of these animals were restudied before and after the administration of cromolyn sodium. Although this drug had no effect on the measurements of mechanics made in the control period, it significantly reduced the ozone-induced changes in mechanics. The increase in RL was 52% of that produced in the first study. The results demonstrated that the ozone injury with its acute and subacute airway sequelae occurs quite rapidly and after very brief exposure. The time course of the change in mechanics and the effects of cromolyn suggest the hypothesis that surface epithelial cells are disrupted, causing subsequent release of bronchoconstricting agents.     

The role of mediators in the response of the canine peripheral lung to 1 ppm ozone

We tested the hypothesis that the in vivo response of the canine peripheral lung to 1 ppm ozone is mediated, in part, by histamine and cyclooxygenase and lipoxygenase products of arachidonic acid metabolism. Ozone was delivered for 5 min to lobar segments through a wedged bronchoscope and resulted in a mean (+/- 1 SE) increase in collateral system resistance (Rcs) of 220.7 +/- 13.8% immediately after exposure. Four 5-min exposures of ozone to the same segments over a 3-h period yielded reproducible Rcs responses, i.e., tolerance to the exposure regimen was not exhibited. Analyses of bronchoalveolar lavage fluid obtained from the isolated segment 1 min after a single exposure to ozone indicated significant increases, compared with control, in mean concentrations of PGD2 (135.3 +/- 33.3 pg/ml versus 47.8 +/- 16.0; p less than 0.025) and histamine (1.43 +/- 0.19 ng/ml versus 1.18 +/- 0.17; p less than 0.05). Additionally, a molecule that exhibited high reactivity with LTB4 antibody was found in greater concentrations in ozone-exposed segments compared to controls (821.5 +/- 206.7 pg/ml versus 437.5 +/- 78.8; p less than 0.05). In contrast, the concentration of TxB2 was not significantly greater in ozone-exposed segments compared to controls (37.2 +/- 6.6 pg/ml versus 33.7 +/- 10.3; p less than 0.05). Cyclooxygenase inhibition (indomethacin, 5 mg/kg, IV) significantly inhibited the Rcs response by 32% (p less than 0.05) and histamine H1-receptor blockade (chlorpheniramine maleate, 5 mg/kg, IV) reduced the response by 30% (p less than 0.05). However, blockade of thromboxane synthetase (UK-37,248, 3 mg/kg, IV) had no significant effect on the ozone-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)