Inhalation exposure to particulate matter in rooms with underfloor air distribution

This work investigated the personal exposure to indoor particulate matters using the intake fraction metric and provided a possible way to trace the particle inhaled from an indoor particle source. A turbulence model validated by the particle measurements in a room with underfloor air distribution (UFAD) system was used to predict the indoor particle concentrations. Inhalation intake fraction of indoor particles was defined and evaluated in two rooms equipped with the UFAD, i.e., the experimental room and a small office. According to the exposure characteristics and a typical respiratory rate, the intake fraction was determined in two rooms with a continuous and episodic (human cough) source of particles, respectively. The findings showed that the well-mixing assumption of indoor air failed to give an accurate estimation of inhalation exposure and the average concentration at return outlet or within the overall room could not relate well the intake fraction to the amount of particle emitted from an indoor source.

RESPIRATORY COMPENSATION MECHANISMS IN THE UPPER AND LOWER RESPIRATORY TRACTS OF AN ANIMAL MODEL AFTER SUBCHRONIC INHALATION EXPOSURE TO FORMALDEHYDE: IMPLICATIONS FOR TOXICOLOGY RISK ASSESSMENT (DEPOSITION, DOSE RECEIVED, RESPONSE)

The potential for significant human populations to experience long-term inhalation of formaldehyde and reports of symptomatology due to this exposure has led to a considerable interest in the toxicologic assessment of risk from subchronic formaldehyde exposures using animal models. Since formaldehyde inhalation depresses certain respiratory parameters in addition to its other forms of toxicity, there is a potential for the alteration of the actual dose received by the exposed individual (and the resulting toxicity) due to this respiratory effect. The respiratory responses to formaldehyde inhalation and the subsequent pattern of deposition were therefore investigated in animals that had received subchronic exposure to the compound, and the potential for changes in the formaldehyde dose received due to long-term inhalation evaluated. Male Sprague-Dawley rats were exposed to either 0, 0.5, 3, or 15 ppm formaldehyde for 6 hours/day, 5 days/week for up to 6 months. The patterns of respiratory response, deposition and the compensation mechanisms involved were then determined in a series of formaldehyde test challenges to both the upper and to the lower respiratory tracts in separate groups of subchronically exposed animals and age-specific controls (four concentration groups, two time points). In both the control and pre-exposed animals, there was a characteristic recovery of respiratory parameters initially depressed by formaldehyde inhalation to at or approaching pre-exposure levels within 10 minutes of the initiation of exposure. Also, formaldehyde deposition was found to remain very high in the upper and lower tracts after long-term exposure. Therefore, there was probably little subsequent effect on the dose received by the exposed individual that was attributable to the repeated exposures. There was a diminished initial minute volume response in test challenges of both the upper and lower tracts of animals that had received at least 16 weeks of exposure to 15 ppm, with compensatory increases in tidal volume in the upper tract and respiratory rate in the lower tract. However, this dose-related effect was probably not relevant to human risk estimation because this formaldehyde dose is in excess of that experienced by human populations. ^

Trace metals in size-fractionated particulate matter in a Portuguese hospital: exposure risks assessment and comparisons with other countries

Hospitals are considered as a special and important type of indoor public place where air quality has significant impacts on potential health outcomes. Information on indoor air quality of these environments, concerning exposures to particulate matter (PM) and related toxicity, is limited though. This work aims to evaluate risks associated with inhalation exposure to ten toxic metals and chlorine (As, Ni, Cr, Cd, Pb, Mn, Se, Ba, Al, Si, and Cl) in coarse (PM2.5–10) and fine (PM2.5) particles in a Portuguese hospital in comparison with studies representative of other countries. Samples were collected during 1 month in one urban hospital; elemental PM characterization was determined by proton-induced X-ray emission. Noncarcinogenic and carcinogenic risks were assessed according to the methodology provided by the United States Environmental Protection Agency (USEPA; Region III Risk-Based Concentration Table) for three different age categories of hospital personnel (adults, >20, and <65 years) and patients (considering nine different age groups, i.e., children of 1–3 years to seniors of >65 years). The estimated noncarcinogenic risks due to occupational inhalation exposure to PM2.5-bound metals ranged from 5.88×10−6 for Se (adults, 55–64 years) to 9.35×10−1 for As (adults, 20–24 years) with total noncarcinogenic risks (sum of all metals) above the safe level for all three age categories. As and Cl (the latter due to its high abundances) were the most important contributors (approximately 90 %) to noncarcinogenic risks. For PM2.5–10, noncarcinogenic risks of all metals were acceptable to all age groups. Concerning carcinogenic risks, for Ni and Pb, they were negligible (<1×10−6) in both PM fractions for all age groups of hospital personnel; potential risks were observed for As and Cr with values in PM2.5 exceeding (up to 62 and 5 times, respectively) USEPA guideline across all age groups; for PM2.5–10, increased excess risks of As and Cr were observed particularly for long-term exposures (adults, 55–64 years). Total carcinogenic risks highly (up to 67 times) exceeded the recommended level for all age groups, thus clearly showing that occupational exposure to metals in fine particles pose significant risks. If the extensive working hours of hospital medical staff were considered, the respective noncarcinogenic and carcinogenic risks were increased, the latter for PM2.5 exceeding the USEPA cumulative guideline of 10−4. For adult patients, the estimated noncarcinogenic and carcinogenic risks were approximately three times higher than for personnel, with particular concerns observed for children and adolescents.

Characterizing emission and breathing-zone concentrations following exposure cases to fluororesin-based waterproofing spray mists.

Measurements and simulations were performed to assess workers' exposure to solvent vapors and aerosols during the waterproofing of a tiled surface. This investigation followed two recent incidents in the same company where workers experienced acute respiratory illness after spraying a stain-repellent resin containing fluorinated polymers on stone-tiled walls and floors. Because the waterproofing activity had been done for years at the tile company without encountering any exposure problems prior to these cases, it was strongly suspected that the incidents were linked to a recent change in the composition of the coating mixture. Experimental measurements and simulations indicated that the emission rate of particles smaller than 10 microm may be estimated at 0.66 mg/sec (SD 0.10) for the old resin and at 0.37 mg/sec (SD 0.04) for the new one. The measurement of the solvent emission rate from surfaces coated with the two resins indicated that shortly after spraying, the emission was in the range of 18 to 20 mg/sec x m2 and was similar for both products. Solvent and overspray emission rates were introduced in a two-zone compartment model. The results obtained in the near-field indicate significant exposure to overspray mist (7 and 34 mg/m3 for new resin) and solvent vapors (80 to 350 ppm for the new resin). It was also shown that the introduction of the new resin tended to significantly decrease the levels of solvents and particulates in the workers' breathing zone. These results strongly suggest that cases of acute respiratory illness are related to the specific toxicity of the fluorinated polymer itself. The fact that the same polymer is used in various commercial products raises concern regarding other possible occupational and domestic exposures.

Évaluation des niveaux d’éthanolémie résultant de l’exposition à l’éthanol par inhalation : études chez des volontaires et modélisation toxicocinétique

Un modèle pharmacocinétique à base physiologique (PBPK) d’exposition par inhalation à l’éthanol a antérieurement été développé en se basant sur des données provenant d’une étude chez des volontaires exposés par inhalation à plus de 5000 ppm. Cependant, une incertitude persiste sur la capacité du modèle PBPK à prédire les niveaux d’éthanolémie pour des expositions à de faibles concentrations. Ces niveaux sont fréquemment rencontrés par une large partie de la population et des travailleurs suite à l’utilisation de produits tels que les vernis et les solutions hydroalcooliques (SHA). Il est ainsi nécessaire de vérifier la validité du modèle existant et de déterminer l’exposition interne à l’éthanol dans de telles conditions. Les objectifs du mémoire sont donc 1) de documenter les niveaux d’éthanolémie résultant de l’exposition par inhalation à de faibles concentrations d’éthanol (i.e., ≤ 1000 ppm) et de valider/raffiner le modèle PBPK existant pour ces concentrations ; et 2) de déterminer les concentrations d’éthanol atmosphérique provenant d’utilisation de SHA et de vernis et de prédire les niveaux d’éthanolémie découlant de leur utilisation. Les données toxicocinétiques récoltées chez des volontaires nous suggèrent qu’il est insuffisant de limiter au foie la clairance métabolique de l’éthanol lors d’exposition à de faibles niveaux d’éthanol, contrairement aux expositions à de plus forts niveaux. De plus, il a clairement été démontré qu’un effort physique léger (50 W) influençait à la hausse (2-3 fois) l’éthanolémie des volontaires exposés à 750 ppm. L’ajout au modèle PBPK d’une clairance métabolique de haute affinité et de faible capacité associée aux tissus richement perfusés a permis de simuler plus adéquatement la cinétique de l’éthanolémie pour des expositions à des concentrations inférieures à 1000 ppm. Des mesures de concentrations d’éthanol dans l’air inhalé générées lors d’utilisation de SHA et de vernis ont permis de simuler des expositions lors de l’utilisation de ces produits. Pour l’utilisation de 1,5 g et 3 g de SHA dans un local peu ventilé, des concentrations sanguines maximales (Cmax) de 0.383 et 0.366 mg.L-1 ont été respectivement simulées. Dans un local bien ventilé, les Cmax simulées étaient de 0.264 et 0.414 mg.L-1. Selon les simulations, une application de vernis résulterait en une Cmax respectivement de 0.719 mg.L-1 et de 0.729 mg.L-1, chez les hommes et femmes. Les Cmax sanguines d’éthanol estimées suites aux différentes simulations sont inférieures à la concentration toxique pour les humains (100 mg.L-1). Ainsi, de telles expositions ne semblent pas être un danger pour la santé. Les résultats de cette étude ont permis de mieux décrire et comprendre les processus d’élimination de l’éthanol à faibles doses et permettront de raffiner l’évaluation du risque associé à l’inhalation chronique de faibles niveaux d’éthanol pour la population, particulièrement chez les travailleurs.

Influence of N-Hexane Inhalation on the Enantioselective Pharmacokinetics and Metabolism of Verapamil in Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.68). In animals exposed to gasoline, we observed an increase in AUC0-∞ for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Chirality 25:206-210, 2013. © 2013 Wiley Periodicals, Inc. Copyright © 2013 Wiley Periodicals, Inc.

Exposure of children to ultrafine particles in primary schools in Portugal

Children spend a large part of their time at schools, which might be reflected as chronic exposure. Ultrafine particles (UFP) are generally associated with a more severe toxicity compared to fine and coarse particles, due to their ability to penetrate cell membranes. In addition, children tend to be more susceptible to UFP-mediated toxicity compared to adults, due to various factors including undeveloped immune and respiratory systems and inhalation rates. Thus, the purpose of this study was to determine indoor UFP number concentrations in Portuguese primary schools. Ultrafine particles were sampled between January and March 2014 in 10 public primary schools (35 classrooms) located in Porto, Portugal. Overall, the average indoor UFP number concentrations were not significantly different from outdoor concentrations (8.69 × 10(3) vs. 9.25 × 10(3) pt/cm(3), respectively; considering 6.5 h of indoor occupancy). Classrooms with distinct characteristics showed different trends of indoor UFP concentrations. The levels of carbon dioxide were negatively correlated with indoor UFP concentrations. Occupational density was significantly and positively correlated with UFP concentrations. Although the obtained results need to be interpreted with caution since there are no guidelines for UFP levels, special attention needs to be given to source control strategies in order to reduce major particle emissions and ensure good indoor air quality.

Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality.

BACKGROUND: The respiratory tract is a major target of exposure to air pollutants, and respiratory diseases are associated with both short- and long-term exposures. We hypothesized that improved air quality in North Carolina was associated with reduced rates of death from respiratory diseases in local populations. MATERIALS AND METHODS: We analyzed the trends of emphysema, asthma, and pneumonia mortality and changes of the levels of ozone, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and particulate matters (PM2.5 and PM10) using monthly data measurements from air-monitoring stations in North Carolina in 1993-2010. The log-linear model was used to evaluate associations between air-pollutant levels and age-adjusted death rates (per 100,000 of population) calculated for 5-year age-groups and for standard 2000 North Carolina population. The studied associations were adjusted by age group-specific smoking prevalence and seasonal fluctuations of disease-specific respiratory deaths. RESULTS: Decline in emphysema deaths was associated with decreasing levels of SO2 and CO in the air, decline in asthma deaths-with lower SO2, CO, and PM10 levels, and decline in pneumonia deaths-with lower levels of SO2. Sensitivity analyses were performed to study potential effects of the change from International Classification of Diseases (ICD)-9 to ICD-10 codes, the effects of air pollutants on mortality during summer and winter, the impact of approach when only the underlying causes of deaths were used, and when mortality and air-quality data were analyzed on the county level. In each case, the results of sensitivity analyses demonstrated stability. The importance of analysis of pneumonia as an underlying cause of death was also highlighted. CONCLUSION: Significant associations were observed between decreasing death rates of emphysema, asthma, and pneumonia and decreases in levels of ambient air pollutants in North Carolina.

Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis

Background Person-to-person transmission of respiratory pathogens, including Pseudomonas aeruginosa, is a challenge facing many cystic fibrosis (CF) centres. Viable P aeruginosa are contained in aerosols produced during coughing, raising the possibility of airborne transmission.

Methods Using purpose-built equipment, we measured viable P aeruginosa in cough aerosols at 1, 2 and 4 m from the subject (distance) and after allowing aerosols to age for 5, 15 and 45 min in a slowly rotating drum to minimise gravitational settling and inertial impaction (duration). Aerosol particles were captured and sized employing an Anderson Impactor and cultured using conventional microbiology. Sputum was also cultured and lung function and respiratory muscle strength measured.

Results Nineteen patients with CF, mean age 25.8 (SD 9.2) years, chronically infected with P aeruginosa, and 10 healthy controls, 26.5 (8.7) years, participated. Viable P aeruginosa were detected in cough aerosols from all patients with CF, but not from controls; travelling 4 m in 17/18 (94%) and persisting for 45 min in 14/18 (78%) of the CF group. Marked inter-subject heterogeneity of P aeruginosa aerosol colony counts was seen and correlated strongly (r=0.73-0.90) with sputum bacterial loads. Modelling decay of viable P aeruginosa in a clinic room suggested that at the recommended ventilation rate of two air changes per hour almost 50 min were required for 90% to be removed after an infected patient left the room.

Conclusions: Viable P aeruginosa in cough aerosols travel further and last longer than recognised previously, providing additional evidence of airborne transmission between patients with CF.

Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis

BACKGROUND: Pseudomonas aeruginosa is the most common bacterial pathogen in patients with cystic fibrosis (CF). Current infection control guidelines aim to prevent transmission via contact and respiratory droplet routes and do not consider the possibility of airborne transmission. It was hypothesised that subjects with CF produce viable respirable bacterial aerosols with coughing.

METHODS: A cross-sectional study was undertaken of 15 children and 13 adults with CF, 26 chronically infected with P aeruginosa. A cough aerosol sampling system enabled fractioning of respiratory particles of different sizes and culture of viable Gram-negative non-fermentative bacteria. Cough aerosols were collected during 5 min of voluntary coughing and during a sputum induction procedure when tolerated. Standardised quantitative culture and genotyping techniques were used.

RESULTS: P aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <or=3.3 microm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).

CONCLUSION: During coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.

Levels and risks of particulate-bound PAHs in indoor air influenced by tobacco smoke: a field measurement

Considering tobacco smoke as one of the most health-relevant indoor sources, the aim of this work was to further understand its negative impacts on human health. The specific objectives of this work were to evaluate the levels of particulate-bound PAHs in smoking and non-smoking homes and to assess the risks associated with inhalation exposure to these compounds. The developed work concerned the application of the toxicity equivalency factors approach (including the estimation of the lifetime lung cancer risks, WHO) and the methodology established by USEPA (considering three different age categories) to 18 PAHs detected in inhalable (PM10) and fine (PM2.5) particles at two homes. The total concentrations of 18 PAHs (ΣPAHs) was 17.1 and 16.6 ng m−3 in PM10 and PM2.5 at smoking home and 7.60 and 7.16 ng m−3 in PM10 and PM2.5 at non-smoking one. Compounds with five and six rings composed the majority of the particulate PAHs content (i.e., 73 and 78 % of ΣPAHs at the smoking and non-smoking home, respectively). Target carcinogenic risks exceeded USEPA health-based guideline at smoking home for 2 different age categories. Estimated values of lifetime lung cancer risks largely exceeded (68–200 times) the health-based guideline levels at both homes thus demonstrating that long-term exposure to PAHs at the respective levels would eventually cause risk of developing cancer. The high determined values of cancer risks in the absence of smoking were probably caused by contribution of PAHs from outdoor sources.

Ultrafine Particles in Ambient Air of an Urban Area: Dose Implications for Elderly

Due to their detrimental effects on human health, the scientific interest in ultrafine particles (UFP) has been increasing, but available information is far from comprehensive. Compared to the remaining population, the elderly are potentially highly susceptible to the effects of outdoor air pollution. Thus, this study aimed to (1) determine the levels of outdoor pollutants in an urban area with emphasis on UFP concentrations and (2) estimate the respective dose rates of exposure for elderly populations. UFP were continuously measured over 3 weeks at 3 sites in north Portugal: 2 urban (U1 and U2) and 1 rural used as reference (R1). Meteorological parameters and outdoor pollutants including particulate matter (PM10), ozone (O3), nitric oxide (NO), and nitrogen dioxide (NO2) were also measured. The dose rates of inhalation exposure to UFP were estimated for three different elderly age categories: 64–70, 71–80, and >81 years. Over the sampling period levels of PM10, O3 and NO2 were in compliance with European legislation. Mean UFP were 1.7 × 104 and 1.2 × 104 particles/cm3 at U1 and U2, respectively, whereas at rural site levels were 20–70% lower (mean of 1 ×104 particles/cm3). Vehicular traffic and local emissions were the predominant identified sources of UFP at urban sites. In addition, results of correlation analysis showed that UFP were meteorologically dependent. Exposure dose rates were 1.2- to 1.4-fold higher at urban than reference sites with the highest levels noted for adults at 71–80 yr, attributed mainly to higher inhalation rates.

Caractérisation de la composante toxicocinétique du facteur d’ajustement pour la variabilité interindividuelle utilisé en analyse du risque toxicologique

Un facteur d’incertitude de 10 est utilisé par défaut lors de l’élaboration des valeurs toxicologiques de référence en santé environnementale, afin de tenir compte de la variabilité interindividuelle dans la population. La composante toxicocinétique de cette variabilité correspond à racine de 10, soit 3,16. Sa validité a auparavant été étudiée sur la base de données pharmaceutiques colligées auprès de diverses populations (adultes, enfants, aînés). Ainsi, il est possible de comparer la valeur de 3,16 au Facteur d’ajustement pour la cinétique humaine (FACH), qui constitue le rapport entre un centile élevé (ex. : 95e) de la distribution de la dose interne dans des sous-groupes présumés sensibles et sa médiane chez l’adulte, ou encore à l’intérieur d’une population générale. Toutefois, les données expérimentales humaines sur les polluants environnementaux sont rares. De plus, ces substances ont généralement des propriétés sensiblement différentes de celles des médicaments. Il est donc difficile de valider, pour les polluants, les estimations faites à partir des données sur les médicaments. Pour résoudre ce problème, la modélisation toxicocinétique à base physiologique (TCBP) a été utilisée pour simuler la variabilité interindividuelle des doses internes lors de l’exposition aux polluants. Cependant, les études réalisées à ce jour n’ont que peu permis d’évaluer l’impact des conditions d’exposition (c.-à-d. voie, durée, intensité), des propriétés physico/biochimiques des polluants, et des caractéristiques de la population exposée sur la valeur du FACH et donc la validité de la valeur par défaut de 3,16. Les travaux de la présente thèse visent à combler ces lacunes. À l’aide de simulations de Monte-Carlo, un modèle TCBP a d’abord été utilisé pour simuler la variabilité interindividuelle des doses internes (c.-à-d. chez les adultes, ainés, enfants, femmes enceintes) de contaminants de l’eau lors d’une exposition par voie orale, respiratoire, ou cutanée. Dans un deuxième temps, un tel modèle a été utilisé pour simuler cette variabilité lors de l’inhalation de contaminants à intensité et durée variables. Ensuite, un algorithme toxicocinétique à l’équilibre probabiliste a été utilisé pour estimer la variabilité interindividuelle des doses internes lors d’expositions chroniques à des contaminants hypothétiques aux propriétés physico/biochimiques variables. Ainsi, les propriétés de volatilité, de fraction métabolisée, de voie métabolique empruntée ainsi que de biodisponibilité orale ont fait l’objet d’analyses spécifiques. Finalement, l’impact du référent considéré et des caractéristiques démographiques sur la valeur du FACH lors de l’inhalation chronique a été évalué, en ayant recours également à un algorithme toxicocinétique à l’équilibre. Les distributions de doses internes générées dans les divers scénarios élaborés ont permis de calculer dans chaque cas le FACH selon l’approche décrite plus haut. Cette étude a mis en lumière les divers déterminants de la sensibilité toxicocinétique selon le sous-groupe et la mesure de dose interne considérée. Elle a permis de caractériser les déterminants du FACH et donc les cas où ce dernier dépasse la valeur par défaut de 3,16 (jusqu’à 28,3), observés presqu’uniquement chez les nouveau-nés et en fonction de la substance mère. Cette thèse contribue à améliorer les connaissances dans le domaine de l’analyse du risque toxicologique en caractérisant le FACH selon diverses considérations.

Détermination du béryllium dans les cheveux humains non exposés, les poils et les os de souris exposées à des poussières de béryllium

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal