Polycyclic aromatic hydrocarbons (PAHs) are environmental and occupational carcinogens that are produced by the incomplete combustion of organic material, such as from the burning of tobacco, coal, and petroleum products. In addition to causing cancer, exposure to PAHs is hypothesized to contribute to atherosclerosis and to lead to increased incidence rates of cardiovascular disease in populations. Considering the number of deaths attributable to tobacco smoke exposure, ambient air pollution, and occupational hazards, PAHs may be a significant contributor to the prevalence of cardiovascular disease in human populations. However, a clear exposure-response relationship between PAHs and measures of cardiovascular disease has not been demonstrated. While PAH exposure has been shown to be associated with indicators of cardiovascular disease in research animals, this relationship has not been studied comprehensively in human populations. Using data from the continuous National Health and Nutrition Examination Surveys (NHANES) 1999 - 2004 of a representative sample of the entire US civilian population, this study investigated predictors of total body burden of PAHs and associations between urinary metabolites of PAHs and biomarkers of cardiovascular disease in 4,492 study participants aged 20 years and older. Using various analytic approaches, this research project identified tobacco smoke exposure as a significant predictor of urinary levels of low molecular weight PAHs but not as a predictor of urinary levels of high molecular weight PAHs in a large population of individuals without known occupational exposure to PAHs. Worker occupational category was not associated with urinary levels of any PAH metabolites. The results of this study also indicate a possible association between exposure to PAHs and the development of cardiovascular disease in humans. Levels of multiple metabolites of specific PAHs, naphthalene, fluorene, and phenanthrene were significantly associated with increases in total cholesterol, triglycerides, WBC count, and C-reactive protein levels. Additionally, this study examined the utility of factor analysis for data reduction of 23 urinary PAH metabolites to two latent factors representing low and high molecular weight PAHs to streamline investigations of the associations of PAH exposures with various health outcomes. Results of this study suggest mechanisms by which PAH exposure contributes to the burden of cardiovascular disease on human populations and the methods by which human body burden on PAHs can be measured.

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Introduction. La fumée secondaire est considérée comme un agent neurotoxique. À ce jour, la littérature traitant des liens entre l’exposition à la fumée secondaire à l’enfance et les comportements antisociaux repose majoritairement sur des devis transversaux ou porte sur la période développementale de l’enfance. Objectif. D’une part, nous souhaitons repousser l’âge auquel les comportements antisociaux sont mesurés en le portant à la préadolescence. De plus, nous souhaitons utiliser des données autorapportées afin d’utiliser une mesure possiblement plus valide des comportements antisociaux. Finalement, nous souhaitons confirmer les résultats longitudinaux précédemment rapportés par les parents ou les enseignants à l’âge de 10 ans. Méthode. Les parents de 1035 enfants ayant participé à l’Étude longitudinale des enfants du Québec ont rapporté si au moins un individu fumait au domicile (entre l’âge d’un an et demi et sept ans). Les variables dépendantes autorévélées (mesurées à douze ans) comprenaient les problèmes de conduite, l’agressivité proactive, l’agressivité réactive, l’indiscipline scolaire et le risque de décrochage. Résultats. Après l’inclusion des variables de contrôle, nous avons observé que l’exposition à la fumée secondaire est prospectivement associée aux problèmes de conduite, l’agressivité proactive, l’agressivité réactive, l’indiscipline scolaire et le risque de décrochage autorévélés. Discussion. Les jeunes exposés à la fumée secondaire à l’enfance rapportent avoir plus de comportements antisociaux. Nos résultats corroborent les recommandations du American Surgeon’s General indiquant qu’aucune exposition à la fumée secondaire ne peut être considérée sécuritaire à l’enfance. / Introduction. Secondhand smoke is considered a developmental neurotoxicant. Up to this day, research on secondhand smoke and later antisocial behavior has remained cross-sectional or in the developmental period of childhood. Objective. We sough to extend previous research by extending to age 12 our prospective associational model. Also, we use self-reported data for validity reasons and to cross-match previous research using parent and teacher-rated data at age 10. Method. Parents reported the amount of household smoke exposure (between ages 1.5 and 7) for 1035 children from the Quebec Longitudinal Study of Child Development. Main outcome measures include self-reported conduct problems, proactive aggression, reactive aggression, dropout risk, and school indiscipline at age 12. Results. After adjusting for potential confounders, we observed that secondhand smoke is prospectively associated to conduct problems, proactive and reactive aggression, school indiscipline, and dropout risk. Discussion. Children exposed to household smoke reported increased risks of reporting antisocial behavior at age 12. Our findings corroborate the recommendation of the American Surgeon’s General that no smoke exposure can be considered safe.

<p> Lung disease is the leading threat to human health worldwide. In particular, two threats are responsible for the majority of the pulmonary disease burden: infection and tobacco smoke exposure. Efforts to combat these diseases have been hampered by gaps in our understanding of the complex interactions between environmental threats and the host's own immune defences. Indeed, much of the pulmonary disease burden should be ascribed not to direct smoke-, virus-or bacteria-induced damage, but to maladaptive host defence responses against these threats. This is an understudied topic. Efforts to redress this deficiency have been hampered by the lack of available animal models. Thus, the present studies developed and examined models of Heterologous pulmonary infection, in which hosts must defend against two different infections, and of tobacco smoke exposure. In the first study, a critical role for MIP-2 driven pulmonary neutrophilia was elucidated in the pathology associated with bacterial superinfection of influenza virus infection. This study further demonstrated that the timing and sequence in which pathogens were encountered played important roles in determining the outcome of disease, and that viral and bacterial infections have different but long-lived impacts on alveolar macrophages. In the second study, it was determined that cigarette smoke exposure impacts host defence without exhausting T-or B-cells. Collectively, these studies have advanced our understanding of complex lung pathologies, and suggest an important role for the innate immune system in mediating such diseases. </p> / Thesis / Doctor of Philosophy (PhD)

Biological markers (i.e., biomarkers) are essential in clinical and epidemiological studies as they may provide mechanistic insights into the developmental origins of disease, as well as improve diagnostic testing and risk assessment for disease prevention. However, major challenges remain due to the lack of rapid yet selective analytical methods for high throughput screening that are also amenable to volume-restricted specimens. This thesis includes two major research themes that take advantage of capillary electrophoresis (CE) separations, including (1) the targeted analysis of urinary iodide and thiocyanate for assessment of nutritional adequacy and tobacco smoke exposures in the population, and (2) the discovery of new biomarkers in sweat specimens that may improve universal newborn screening programs for cystic fibrosis (CF) infants beyond impaired chloride transport. Chapter II examines the prevalence and risk factors associated with iodine deficiency in 24 h urine samples collected from 800 participants across four clinical sites in Canada as part of the Prospective Urban and Rural Epidemiological (PURE) study when using CE with UV detection in conjunction with sample self-stacking. Importantly, regional variations in iodine status were revealed with participants from Quebec City and Vancouver at greater risk for iodine deficiency than Hamilton and Ottawa. Overall, iodine supplement use, thyroxine prescription, urinary sodium excretion, and self-reported dairy intake were found to be protective factors against iodine deficiency. Chapter III applied a validated CE assay to measure urinary thiocyanate as a biomarker of tobacco smoke and dietary exposures in an international cohort of 1000 participants from the PURE study spanning 14 countries with varied income status, smoking habits, and diet quality. Current smokers residing in high-income countries had the highest extent of cyanide exposure indicative of greater harms from tobacco smoke compared to middle- and low-income countries after adjusting for smoking intensity and other covariates. Chapter IV introduces a rapid CE method with indirect UV detection to simultaneously measure sweat chloride and bicarbonate from presumptive CF infants’ residual sweat samples. Although bicarbonate did not provide clinical value in neonatal CF diagnosis, sweat chloride testing by CE may reduce test failure rates due to insufficient volumes from infants in a clinical setting. Lastly, Chapter V applied an untargeted strategy to characterize the sweat metabolome from presumptive CF infants when using multisegment injection-capillary electrophoresis-mass spectrometry (MSI-CE-MS). A panel of sweat metabolites were found to discriminate CF from non-CF (i.e., unaffected carriers) infants, including aspartic acid, glutamine, oxoproline, and pilocarpic acid, which also correlated with sweat chloride. The clinical utility of these sweat metabolites to prognosticate late-onset CF infants from indeterminate sweat chloride test results was also explored. In summary, this thesis contributes innovative separation methods for biomarker screening and discovery in clinical and epidemiological studies for the prevention and early treatment of human diseases that benefit from optimal nutrition. / Dissertation / Doctor of Philosophy (PhD)