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Background: Traffic-related air pollution may contribute to cardiovascular morbidity. In urban areas, exposures during physical activity are of interest owing to increased breathing rates and close proximity to vehicle emissions., Methods: We conducted a cross-over study among 53 healthy non-smoking women in Montreal, Canada during the summer of 2013. Women were exposed to traffic pollutants for 2-hours on three separate occasions during cycling on high and low-traffic routes as well as indoors. Personal air pollution exposures (PM(2.5), ultrafine particles (UFP), black carbon, NO₂, and O₃) were evaluated along each route and linear mixed-effects models with random subject intercepts were used to estimate the impact of air pollutants on acute changes in blood pressure, heart rate variability, and micro-vascular function in the hours immediately following exposure. Single and multi-pollutant models were examined and potential effect modification by mean regional air pollution concentrations (PM(2.5), NO₂, and O₃) was explored for the 24-hour and 5-day periods preceding exposure., Results: In total, 143 exposure routes were completed. Each interquartile increase (10,850/cm³) in UFP exposure was associated with a 4.91% (95% CI: -9.31, -0.512) decrease in reactive hyperemia index (a measure of micro-vascular function) and each 24 ppb increase in O₃ exposure corresponded to a 2.49% (95% CI: 0.141, 4.84) increase in systolic blood pressure and a 3.26% (95% CI: 0.0117, 6.51) increase in diastolic blood pressure 3-hours after exposure. Personal exposure to PM(2.5) was associated with decreases in HRV measures reflecting parasympathetic modulation of the heart and regional PM(2.5) concentrations modified these relationships (p < 0.05). In particular, stronger inverse associations were observed when regional PM(2.5) was higher on the days prior to the study period. Regional PM(2.5) also modified the impact of personal O₃ on the standard deviation of normal to normal intervals (SDNN) (p < 0.05): a significant inverse relationship was observed when regional PM(2.5) was low prior to study periods and a significant positive relationship was observed when regional PM(2.5) was high., Conclusion: Exposure to traffic pollution may contribute to acute changes in blood pressure, autonomic and micro-vascular function in women. Regional air pollution concentrations may modify the impact of these exposures on autonomic function.

In vitro models are promising approaches to investigate the adverse effects and the mode of action of air pollutants on the respiratory tract. We designed a dynamic system that allows the single or repeated exposure of cultured cells to two major indoor air gaseous pollutants, formaldehyde (HCHO) and nitrogen dioxide (NO2), alone or as a mixture. In this system, the Calu-3 human bronchial epithelial cell line was exposed at the air-liquid interface (ALI) or submerged by culture medium to synthetic air or to target concentrations of HCHO and/or NO2 once or on 4 consecutive days before assessment of cell viability and necrosis, IL-6 and IL-8 release and trans-epithelial electrical resistance. Our data showed that whereas the ALI method can be used for single short-term exposures only, the submerged method provides the possibility to expose Calu-3 cells in a repeated manner. As well, we found that repeated exposures of the cells to HCHO and NO2 at concentrations that can be found indoors triggered a significant decrease in cell metabolism and an increase in IL-8 release that were not evoked by a single exposure. Thus, our work highlights the fact that the development of systems and methods that allow repeated exposures of cultured cells to gaseous compounds in mixtures is of major interest to evaluate the impact of air pollution on the respiratory tract., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Several recent studies have reported significant health effects of air pollution even at low levels of air pollutants, but in most of these studies linear non-threshold relations were assumed., Aims: To investigate the NO2 mortality dose-response association in nine cities participating in the APHEA-2 project using two different methods: the meta-smooth and the cubic spline method., Methods: The meta-smooth method developed by Schwartz and Zanobetti is based on combining individual city non-parametric smooth curves; the cubic spline method developed within the APHEA-2 project combines individual city estimates of cubic spline shaped dose-response relations. The meta-smooth method is easier and faster to implement, but the cubic spline method is more flexible for further investigation of possible heterogeneity in the dose-response curves among cities., Results: In the range of the pollutant common to all cities the two methods gave similar and comparable curves. Using the cubic spline method it was found that smoking prevalence acts as an effect modifier with larger NO2 effects on mortality at lower smoking prevalence., Conclusions: The NO2-mortality association in the cities included in the present analysis, could be adequately estimated using the linear model. However, investigation of the city specific dose-response curves should precede the application of linear models.

We investigated the effect of intratracheal injections of an extract of suspended particulate matter (SPM) obtained from the urban ambient air of Tokyo, upon the development of proliferative lesions of pulmonary endocrine cells (PECs) in the rat. We also examined the modification effects of nitrogen dioxide, sulfur dioxide, or both of them on the PEC lesions. Male F344 rats were divided into six experimental groups of 5 animals each. Twenty animals were treated with intratracheal instillations of SPM admixed with carbon once a week for 4 weeks with or without additional gaseous exposure (6 ppm nitrogen dioxide or 4 ppm sulfur dioxide) 16 hrs a day for 11 months. Five animals were given intratracheal injections of carbon suspended in saline and the other five were untreated. The subcardiac lobes of the right lung were fixed with 4% paraformaldehyde, and embedded in paraffin. PEC hyperplasias and papillomas were counted in 200 serial sections, 4 microns thick. The average incidences of PEC hyperplasia in the untreated animals and in those treated with carbon were 194 and 200/cm3, respectively. The average incidences of PEC hyperplasia in the animals exposed to SPM tar only, SPM tar plus nitrogen dioxide and sulfur dioxide, SPM tar with nitrogen dioxide and SPM tar with sulfur dioxide were 376, 378, 372 and 349/cm3, respectively. These were significantly higher than the levels of the control animals, and additional gaseous stimuli had no effect on the incidence of PEC hyperplasia. Besides PEC hyperplasia, a few PEC papillomas were found in the animals treated with SPM tar, regardless of gaseous exposure, but in the control animals no papilloma was evident. Thus, compounds in airborne particulates are considered to be responsible for the development of PEC hyperplasias and papillomas.

Immune hypersensitivity to house dust mite antigen (HDM) is a frequent cause of respiratory allergy. The objective of this study was to determine whether exposure to NO2, a common indoor air pollutant, modulates immune responses to HDM and influences immune-mediated lung disease. Brown Norway rats were immunized ip with 100 micrograms semipurified antigen and Bordetella pertussis adjuvant and challenged 2 weeks later with an intratracheal injection of 50 micrograms of a crude antigen preparation. Exposure to 5 ppm NO2 for 3 hr after both immunization and challenge procedures resulted in significantly higher levels of antigen-specific serum IgE, local IgA, IgG, and IgE antibody than air controls, and increased numbers of inflammatory cells in the lungs. Lymphocyte responsiveness to antigen in the spleen and MLN was also significantly higher in NO2-exposed animals. These data show that exposure to a common air pollutant can upregulate specific immune responses and subsequent immune-mediated pulmonary inflammation.

Nitrogen dioxide (NO2) is one of a number of nitrogen compounds that are by-products of combustion and occur in domestic environments following the use of gas or other fuels for heating and cooking. In this study, we examined the effect of two levels of NO2 on symptoms, lung function and airway hyperresponsiveness (AHR) in asthmatic adults and children. In addition, in the same subjects, we examined the effects of the same levels of NO2 mixed with combustion by-products from a gas space heater. The subjects were nine adults, aged 19-65 yrs, and 11 children, aged 7-15 yrs, with diagnosed asthma which was severe enough to require daily medication. All subjects had demonstrable AHR to histamine. Exposures were for 1 h on five separate occasions, 1 week apart, to: 1) ambient air, drawn from outside the building; 2) 0.3 parts per million (ppm) NO2 in ambient air; 3) 0.6 ppm NO2 in ambient air; 4) ambient air+combustion by-products+NO2 to give a total of 0.3 ppm; and 5) ambient air+combustion by-products+NO2 to give a total of 0.6 ppm. Effects were measured as changes in lung function and symptoms during and 1 h after exposure, in AHR 1 h and 1 week after exposure, and in lung function and symptoms during the week following exposure. Exposure to NO2 either in ambient air or mixed with combustion by-products from a gas heater, had no significant effect on symptoms or lung function in adults or in children. There was a small, but statistically significant, increase in AHR after exposure to 0.6 ppm NO2 in ambient air. However, there was no effect of 0.6 ppm NO2 on AHR when the combustion by-products were included in the test atmosphere nor of 0.3 ppm NO2 under either exposure condition. We conclude that a 1 h exposure to 0.3 or 0.6 ppm NO2 has no clinically important effect on the airways of asthmatic adults or children, but that 0.6 ppm may cause a slight increase in airway hyperresponsiveness.

In the present study utilizing male Hartley guinea pigs, we investigated (1) the concentration and time dependency of the effects of subchronic exposure to nitrogen dioxide (NO2) on airway responsiveness and (2) the concentration and time dependency of the effects on specific airway resistance under room air (SRaw0). Animals were exposed to filtered air, 0.06, 0.5, 1.0, 2.0, or 4.0 ppm NO2 for 6 and 12 weeks (24 hr/day). Airway responsiveness and SRaw0 were determined 1 week before the beginning of exposure at 10 weeks of age and on the day of termination of the exposure. Our results revealed that (1) subchronic exposure to NO2 induces airway hyperresponsiveness, both concentration and time dependently, (2) such exposure also induces an increase in SRaw0, both concentration and time dependently, and (3) subsequent to the airway hyperresponsiveness induced by NO2 is an increase in the SRaw0. Therefore, NO2 could be a potent risk factor for alteration of pulmonary function and airway responsiveness.

Both peak flow decrements in children at summer camps and increased hospital admissions for asthma have been associated with summer "acid haze," which is composed of ozone and various acidic species. The objective of this study was to investigate the pulmonary effects of acid summer haze in a controlled laboratory setting. Twenty-eight adolescent subjects with allergic asthma, exercise-induced bronchospasm, and a positive response to a standardized methacholine challenge enrolled in the study; 22 completed the study. Each subject inhaled one of four test atmospheres by mouthpiece on two consecutive days. The order of exposure to the four test atmospheres was assigned via a random protocol: air, oxidants (0.12 parts per million [ppm]* ozone plus 0.30 ppm nitrogen dioxide), oxidants plus sulfuric acid at 70 micrograms/m3 of air, or oxidants plus 0.05 ppm nitric acid. Exposure to each of the different atmospheres was separated by at least one week. The exposures were carried out during alternating 15-minute periods of rest and moderate exercise for a total exposure period of 90 minutes per day. Pulmonary function was measured before and after exposure on both test days and again on the third day as a follow-up measurement. A postexposure methacholine challenge was performed on Day 3. Low methacholine concentrations were chosen for the postexposure challenge to avoid provoking a response. The protocol was designed to detect subtle changes in airway reactivity. The statistical significance of the pulmonary function values was tested using paired t tests. First, we compared the difference between baseline and postexposure measurements after air exposure on Day 1 with the differences between baseline and postexposure measurements after Day 1 exposure to each of the other three atmospheres. Second, we compared the difference between baseline and postexposure measurements after the Day 2 air exposure with the differences between baseline and postexposure measurements after the Day 2 exposure to each of the pollutant atmospheres. Third, we compared the difference between baseline measurements on Day 1 of each exposure atmosphere with measurements after exposure to the same atmosphere on Day 2 to detect delayed effects. No changes in any of the pulmonary function parameters were statistically significant when compared with changes after clean air exposure. Six subjects left the study because of uncomfortable symptoms associated with the exposures. These all occurred after exposure to pollutant atmospheres and not after exposure to clean air.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhalation toxicology experiments in whole animals have demonstrated a remarkable lack of toxicity of sulfuric acid in the form of respirable aerosols, especially in rats and nonhuman primates. Thus, much of the current experimental emphasis has shifted to the evaluation of the potential health effects of acid aerosols as components of mixtures. Rats have been concurrently exposed to mixtures of ozone or nitrogen dioxide with respirable-sized aerosols of sulfuric acid, ammonium sulfate, or sodium chloride, or to each pollutant individually. Their responses to such exposures have been evaluated by various quantitative biochemical analysis of lung tissue or wash fluids ("lavage fluid") or by quantitative morphological methods ("morphometry"). Such studies have mainly been performed in the acute time frame due to the inherent limitations of the most sensitive assays available and have generally involved exposures for 1 to 9 days, depending on the assays used. Good correlations were found between the most sensitive biochemical indicators of lung damage (protein content of lung lavage fluid or whole lung tissue and lung collagen synthesis rate) and the exposure concentration of oxidant gas present alone or in mixtures with acidic aerosols showing interactive effects. Synergistic interaction between ozone and sulfuric acid aerosol was demonstrated to occur at environmentally relevant concentrations of both pollutants by several of the analytical methods used in this study. Such interactions were demonstrated at concentrations of ozone as low as 0.12 ppm and of sulfuric acid aerosol at concentrations as low as 5 to 20 micrograms/m3.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats were concurrently exposed to mixtures of ozone or nitrogen dioxide and respirable-sized aerosols of sulfuric acid, ammonium sulfate, or sodium chloride, or to each pollutant individually. Their responses to such exposures were evaluated by various quantitative biochemical analyses of lung tissue or lavage fluids, or by morphometric analyses. Such studies were performed in the acute time frame, generally involving exposures of from one to nine days, depending on the assays used. Correlations between the biochemical and morphometric results were examined over a wide range of pollutant concentrations in the exposure chambers. Good correlations were found between the most sensitive biochemical indicators of lung damage--the protein content of lung lavage fluid or whole lung tissue and the rate of lung collagen synthesis--and the morphometric estimation of volume density or volume percent of the centriacinar lung lesion characteristically observed in animals exposed to ozone. Synergistic interaction between ozone and sulfuric acid aerosol was demonstrated to occur at environmentally relevant concentrations of both pollutants by several of the analytical methods used. Such interactions were demonstrated at concentrations of ozone as low as 0.12 parts per million (ppm)2 and of sulfuric acid aerosol at concentrations as low as 5 to 20 micrograms/m3. The acidity of the aerosol is a necessary (and apparently a sufficient) condition for such a synergistic interaction between an oxidant gas and a respirable aerosol to occur. A hitherto unexpected synergistic interaction between nitrogen dioxide and sodium chloride aerosol was found during these studies; it is hypothesized that this was due to formation of their acidic (anhydride) reaction product, nitrosyl chloride, in the chambers during exposure to the mixture. Preliminary experiments treating exposed animals in vivo with various free-radical scavengers suggested that dimethylthiourea, a hydroxyl-radical scavenger, might be protective against effects of ozone on rat lungs. This observation might have mechanistic implications, but further studies will be necessary to determine the significance of these findings.

Whether short-term exposure to low levels of nitrogen dioxide (NO2) enhances airway responsiveness in asthmatic subjects is controversial. Because it is well established that asthma is associated with increased airway responsiveness to another common air pollutant, sulfur dioxide (SO2), we examined whether short-term exposure of asthmatic subjects to 0.3 ppm NO2 potentiates airway responsiveness to inhaled SO2. We exposed nine subjects with clinically stable asthma to 0.3 ppm NO2 or filtered air in an environmental room for 30 min on 2 separate days at least 1 wk apart in a double-blind, randomized fashion. A questionnaire about common symptoms related to inhaled irritants was completed before and immediately after each exposure. Each subject exercised (60 to 80 W) on a cycloergometer during the first 20 min of each exposure. We measured specific airway resistance (SRaw) and FEV1/FVC before, 5 min after, and 1 h after completion of the air or NO2 exposure. The single-breath nitrogen test (SBN2) was also performed before and 1 h after completion of the air or NO2 exposures and closing volume was determined; subsequently, SO2 dose-response curves (0.25 to 4.0 ppm) were performed via a mouthpiece. Each dose of SO2 was inhaled at a minute ventilation of 20 L/min for 4 min and was doubled until SRaw increased by at least 8 U above baseline. The dose of SO2 required to provoke an increase in SRaw of 8 U above baseline was determined by linear interpolation from the dose-response curve (PD8Uso2).(ABSTRACT TRUNCATED AT 250 WORDS)

The study reported herein evaluates the influence of a chronic exposure to an urban pattern of NO2 (continuous baseline exposure of 0.2 ppm, on which were superimposed two 1-h spikes of 0.8 ppm NO2, 5 d/wk) as compared to the baseline exposure to determine the contribution of the spikes to toxicity. Mice were exposed for up to 52 wk with interim examinations. Multivariate analysis of variance revealed a statistically significant treatment effect on infectivity (p = 0.05) and pulmonary function (p = 0.03) parameters. Infectivity mortality of mice in the spiked exposure regimen was significantly greater than that in either the NO2-background-exposed mice or in control mice. Four of the pulmonary function variables exhibited the greatest differences among the treatment groups: end expiratory volume, vital capacity, respiratory-system compliance, and multiple-breath nitrogen washout. Results from the pulmonary-function analyses indicate that the spiked exposures to 0.8 ppm NO2 may have induced a subtle lesion. The chronic study results indicate that the presence of spikes of NO2 is contributing significantly to effects on antibacterial lung defenses and pulmonary function of mice.

An automated animal inhalation exposure facility was designed to conduct chronic exposures of rodents to gaseous pollutants. The facility consisted of 3 walk-in chambers with modular cages to allow for exposure of up to a maximum of 480 mice or 240 adult rats. Critical parameters of operation, such as relative humidity, pollutant concentration, and temperature, were monitored continuously. Failure of the system to maintain parameters within specified limits activated the alarm system. Distribution of test gases in the chambers was evaluated for homogeneity, and the standard deviation was determined to be within +/- 5% of the target concentrations throughout the chamber. The exposure facility was successfully used to expose 720 rats to diurnal patterns of O3 (baseline of 0.06 ppm for 13 h with an exposure peak to 0.25 ppm over 9 h) and NO2 (baseline of 0.5 ppm for 16 h with an exposure peak to 1.5 ppm over 6 h) for a period of 18 mo.

Many studies have been conducted to investigate the effects of different air pollutants on health. Our studies have focused on the effects of nitrogen dioxide (NO2), and recently we reported that inhalation of low levels of NO2 can facilitate cancer cell metastasis. The study described herein utilized the same B16 mouse melanoma metastasis model of previous investigations, but under different NO2 exposure conditions. The results provide further evidence that inhalation of ambient level NO2 (0.4 ppm) or polluted urban ambient air play a role in facilitation of blood-borne cancer cell metastasis. In addition, results show different patterns of melanoma cell distribution in the lungs of NO2- and ambient-air exposed animals. They also indicate that extended periods of clean air between NO2 exposures may diminish the severity of the insult in the less sensitive animals. It is our conclusion that the results provide strong support for the need of improved air quality and for reduction of noxious pollutants in urban ambient air.