Harvard T.H. Chan School of Public Health

Climate change is resulting in heatwaves that are more frequent, severe, and longer lasting, which results in public health threats to both morbidity and mortality. This is especially true in the Northeast United States, where heat-related mortality is projected to potentially triple by the end of the century if adequate climate change mitigation and adaptation strategies are not implemented. The first paper explored how central air conditioning and window air conditioning units were not equally adequate in overcoming high temperature loads indoors, and demonstrated how as thermal decompensation begins, protective behaviors were not widely enacted. The second paper aimed to determine if vital social services are impacted by extreme heat in Boston to help inform future adaptation planning. These results demonstrated that the Boston Police, EMS, and Fire Departments all experience more calls on hot days, with the Fire Department having the greatest relative impact on these days. The third paper used a case-only analysis to compare effect modification by individual, and small-area social and environmental heat-related risk factors on at-home and outside of the home mortality in Boston, MA. Census tracts with a greater proportion of people with limited English proficiency and low-to-no income individuals were more highly represented in those who died during the study period, but area built environment features, like a greater density of street trees and newly renovated buildings were able to reduce the relative odds of death within and outside the home. The fourth research papers aimed to evaluate the spatial distribution of these small-area social and environmental factors that determine heat vulnerability to at-home mortality in Boston, MA. The spatial analysis of these factors in relationship to at-home mortality rates on hot days found that neighborhoods like Roxbury, East Boston, and Dorchester are socially and environmentally vulnerable to a greater at-home mortality rate on hot days, and should be prioritized in heat adaptation planning.

This work is intended to cover the stages of research in environmental epidemiology: beginning with exposure assessment, to determining health effects, to seeing how information can be aggregated from individual studies in order to inform policy through a meta-analysis. In Chapter 1, we describe a model to predict outdoor exposure to ambient Black Carbon (a marker of diesel exhaust) in Massachusetts, Rhode Island and Southern New Hampshire from 2000 to 2012. We built this model using Nu-Support Vector Regression – a machine learning technique which incorporates nonlinear terms and higher order interactions, with appropriate regularization of parameter estimates. Our data consisted of 24,301 measurements from 368 monitors in addition to both spatial and temporal predictors. The 10 fold cross validated R2 of the model was good in both cold (10-fold CV R2 = 0.73) and warm seasons (CV R2 = 0.75). In Chapter 2, we implement a novel approach to estimate the marginal risk of all-cause mortality associated with exposure to PM2.5. We carried out our analyses among approximately 12 million movers enrolled in Medicare between 2000 and 2012 and in a subset of about 10 million movers exposed to less than 12 µg/m3 of PM2.5. In our first analysis we assumed that exposure was randomized and we used a cox model in order to estimate the risk. In our second analysis we did not make the assumption of randomization, but rather used inverse probability weights (IPW) in order to control for confounders. We then ran a cox model in using these weights. We found an increased risk of all-cause mortality of 1.16 (95% Confidence Interval (CI): 1.16 – 1.17) per 10 µg/m3 of PM2.5 in both the first and second analysis. Among movers exposed to less than 12 µg/m3 of PM2.5 the risk was 1.27 (95% CI: 1.26 – 1.27) and 1.26 (95% CI: 1.25 – 1.26) per 10 µg/m3 of PM2.5 in the non-IPW adjusted and IPW adjusted analyses respectively. In Chapter 3, we carried out a meta-analysis for the effect of air pollution on cognitive outcomes in 3 age groups: children aged 5 and younger, children aged 6 and older and among adults aged 55 and older. In the last age group we also looked at the risk of Dementia. We combined results from studies using different pollutants and different tests by adjusting the reported estimated. Among children aged 5 and younger we found a significant pooled estimate for psychomotor development (-4.71, per 10 µg/m3 of PM2.5, 95% CI: -7.25 to -1.09) but not mental development. We did not find a significant pooled estimate for children aged 6 and older. Among older adults we found a significant effect for global cognition (-0.16 per 10 µg/m3 of PM2.5, 95% CI: -0.29 to -0.03) but not for memory. Finally, we found a pooled hazard ratio of 1.48 for Alzheimer’s Disease (95% CI: 0.9 to 2.42) of PM2.5 and a pooled hazard ratio of 1.87 for Dementia (95% CI: 1.22 to 2.87) both per µg/m3 of PM2.5.

Background. Dioxins, furans and polychlorinated biphenyls (PCBs) are persistent organic compounds released into the environment as a result of industrial activity. They disrupt endocrine function, and may have contributed to recent documented worldwide declines in sperm count and fertility (Diamanti-Kandarakis et al., 2009; Bursian, Newsted and Zwiernik, 2011; Zawatski and Lee, 2013; Gore et al., 2015). However, few studies have examined the longitudinal effects of childhood exposure to these chemicals. This work investigates how boys’ exposure to dioxins, furans and PCBs during the critical peripubertal developmental window might affect 1) serum sex hormones throughout adolescence 2) and the pace of pubertal progression. Methods. The Russian Children’s Study measured serum toxic equivalents (TEQs) of dioxins (PCDDs), furans (PCDFs), coplanar PCBs (c-PCBs) and mono-ortho-PCBs (m-PCBs), and serum concentrations of non-dioxin-like PCBs (NDL-PCBs), in 516 boys aged 8-9. We then followed the boys for 11 years, measuring serum sex hormones and testicular volume (TV) biennially through ages 18-19. We used longitudinal mixed methods to model the association of peripubertal serum organochlorines with serum testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) throughout adolescence. We then created population trajectories of pubertal progression by applying Latent Class Growth Modeling (GBTM) to longitudinal measurements of TV. Finally, using ordinal and multinomial logistic models, we examined associations between organochlorines and trajectories of pubertal progression. Results. Peripubertal serum TEQs were associated with 1) mid-pubertal decreases in serum testosterone (PCDD TEQs and c-PCB TEQs); 2) mid-pubertal decreases in serum FSH (PCDD TEQs); and 3) slower pubertal progression (all TEQs), consistent with prior findings linking TEQs to pubertal delays (Burns et al., 2016). On the other hand, peripubertal exposure to NDL-PCBs was associated with early- to mid-pubertal decreases in serum testosterone and FSH, in conjunction with accelerated pubertal progression. The association with accelerated pubertal progression is consistent with prior observations (Burns et al., 2016), though it is unclear how the accompanying declines in sex hormone concentrations fit in. Conclusion. In boys, increased peripubertal exposure to dioxins, furans and PCBs is associated with disruptions in serum testosterone, FSH and LH throughout adolescence, as well as shifts in tempo of pubertal progression.

Recent studies touting the potential long term negative effects of traumatic brain injuries have pushed these injuries in the forefront of public health concern. There is particular concern of whether or not there is a time window where these injuries are more dangerous. Using robust methods, our research suggests that early life head injuries tend to have worse effects on a latent outcome like the development of Parkinson’s disease, as well as on a relatively short term outcome like cognitive function. For both of these outcomes this dissertation evaluated how the timing of head injuries in conjunction with disease onset or cognitive measurement may impact results. But after considering these time effects, a younger age at first head injury was still associated with adverse neurological effects. It is hypothesized that a head injury during key developmental time periods may actually serve to disrupt developmental processes. This disruption in these processes can potentially have both long term and permanent negative effects on brain function.

Environmental epidemiology has begun to investigate attributes of the physical environment in which people live, work and play daily that are associated with health. Features of the environment bear on risk factors for chronic diseases prevalent in the U.S. and elsewhere. For example, physical inactivity, overweight and obesity all profoundly influence downstream health, and the physical environment may provide opportunities to intervene for desirable outcomes. Interventions in the physical environment can complement education and behavior change activities already being pursued, such as incentives to exercise and education on healthy diets. Among these attributes of the physical environment important for health, researchers have begun to study the effects of exposure to nature. Growing evidence seems to suggest that nature (often operationalized as exposure to vegetation, or vegetative density) may positively influence many health endpoints. Another recent exposure of interest is neighborhood noise level, which has been investigated not solely as a cause of annoyance or auditory effects but as a potential contributor to cardiovascular disease. Both of these relatively new research areas provide opportunities for environmental health interventions. The evidence base, however, would benefit from prospective studies in large cohorts. The objective of my doctoral research was to examine the association between these exposures and prevalent risk factors and health outcomes prospectively. Using data from the long-running cohort of professional women, the Nurses’ Health Study, I examined the relationship between surrounding greenness and depression, finding that those who lived in the greenest areas were statistically significantly less likely to develop depression over the course of follow-up. I also considered the relationship between surrounding greenness and incident overweight and obesity in the Nurses’ Health Study II, finding little evidence for an association. Finally, I examined the association between nighttime residential noise level and incident hypertension in the Nurses’ Health Study II. I found that greater noise levels were statistically significantly associated with increased risk for incident hypertension. These studies contribute to our understanding of how attributes of the physical environment may influence health, incorporating information from large prospective cohort studies in the U.S.

Phthalates and parabens are endocrine disrupting chemicals with ubiquitous human exposure. Medication coatings and personal care products (PCPs) are important exposure sources, however, their contribution to men’s exposure as well as health effects are understudied. Dibutyl phthalate (DBP) is used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease. This work presents novel innovative methods to assess whether high-DBP exposure from mesalamine (>1000x background-exposure) altered serum reproductive hormones and semen quality. We took advantage of different mesalamine formulations with/without DBP to conduct a prospective crossover-crossback study (MARS study). We estimated crossover, crossback and carryover effects using multivariable linear mixed effect models. We conclude that high-DBP exposure disrupted serum levels of pituitary-gonadal hormone levels that largely reversed after exposure removal, but only in men with no/short history (< 3 years) of previous high-DBP exposure. However, high-DBP exposure among men with no history of high-DBP mesalamine use led to a reduction, primarily in sperm motility that was not reversed but became more pronounced (carried-over) after removal of exposure for four months. Paradoxically, among men with longer duration of high-DBP exposure, removal of the exposure did not change hormone levels or semen quality, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and spermatogenesis making them insensitive to DBP-exposure changes. Based on this work, we offer recommendations for designing future crossover-crossback studies including longer crossover-crossback durations and different timing of sample collection. In the prospective EARTH cohort study, we assessed PCPs’ contribution to men’s phthalate and paraben exposure. We estimated the changes in urinary concentrations associated with PCP-use using multivariable linear mixed and Tobit mixed regressions. We also estimated weights for each PCP in a weighted binary score regression and modeled the resulting composite weighted PCP-use. We identified ten PCPs of relevance and demonstrated that their use within six hours of urine collection strongly predicted specific phthalate and paraben urinary concentrations. We also offer concise PCP-use information by only asking specific questions about the use of the most relevant PCPs to help future research in decreasing missingness, improving recall, and decreasing misclassification while optimizing research cost and time.

While the link between in utero exposure to environmental chemicals and neurodevelopment has long been of interest to environmental epidemiologists, significant gaps remain in the literature, namely: 1) thousands of chemicals are produced and consumed in the United States every year, only some of which have been examined for neurodevelopmental effects, 2) chemicals are often examined in isolation even though the fetus is exposed to many chemicals at once, leaving the potential for synergistic effects, and 3) the mechanisms by which chemicals affect the brain are not fully elucidated. This dissertation aims to narrow each of these gaps. The first study addresses the first gap by examining the potential adverse neurocognitive effects of acetaminophen, a chemical that has only recently been explored for its neurodevelopmental effects. While previous studies using maternal report of exposure found a negative association with behavioral outcomes, this study, which uses a quantitative biomarker of acetaminophen exposure, finds no association. The second study addresses the second gap by investigating the combined effects of heavy metals and essential micronutrients on cognition and motor ability. It finds a nonlinear association between manganese and motor ability, and several sex-specific associations and interactions. Finally, studies three and four address the third gap by exploring the microbiome as a target of environmental exposures and a potential mediator of the association between chemicals and neurodevelopment. Study three finds that prenatal exposure to polybrominated diphenyl ethers and polychlorinated biphenyls is associated with changes to certain bacterial taxa in mid childhood, indicating the potential for long-term effects on the gut microbiome. The fourth study finds an association between prenatal caffeine exposure and beta diversity as well as specific taxa. Further, adjusting for the relative abundance of these taxa weakens the negative association between caffeine exposure and neurodevelopment measures. This dissertation addresses each of three significant gaps in the environmental epidemiology neurodevelopment literature. It demonstrates the importance of considering multiple exposures concurrently, particularly those that may act through similar mechanisms. Notably, this dissertation proposes the gut microbiome as a novel mechanism by which environmental exposures affect neurodevelopment. This paradigm should inform future environmental epidemiological research.

While the effects of particulate matter (PM) on morbidity and mortality are well-established, the specific properties of PM responsible for these effects are still not completely understood. However, identifying the toxic properties of particles is critical for developing cost-effective air quality standards and ultimately protecting public health. This dissertation investigates the potential health effects of particle radioactivity, a property of airborne particles. We hypothesize that radionuclides attached to PM may have direct health effects by releasing ionizing radiation in the lungs after inhalation and deposition. In our first study, we assessed potential effect modification of radon on PM2.5-associated daily mortality in 108 U.S. cities. First, we estimated city- and season-specific PM2.5 mortality risks using time-series models, and then we regressed these effect estimates against city-level radon concentrations to estimate potential modification by radon. We found that higher mean city-level radon concentrations increased the PM2.5-mortality association in the spring and fall, suggesting that radon may enhance PM2.5 mortality. In our second study, we used time-varying measurements of gross beta radiation to directly estimate the independent health effects of particle radioactivity. Specifically, we evaluated whether short- and intermediate-exposures to particle radioactivity were associated with biomarkers of inflammation and endothelial function in an elderly male cohort. We observed associations between particle radioactivity on C-reactive protein, intercellular adhesion molecule-1 and vascular cell adhesion moleducle-1, suggesting a potential pathway for radiation-induced cardiovascular effects. Finally, we investigated the spatial and temporal variability of particle radioactivity using particle activity concentrations measured by RadNet monitors located in and around Massachusetts. We found a distinct seasonal trend at all monitors, with the highest concentrations occurring in the winter. Using a back-trajectory and clustering analysis, we found that air masses arriving from the west and southwest had the highest concentrations of beta radiation. Prevailing air mass trajectories appeared to strongly influence seasonal trends in particle radioactivity. We also investigated the role of different meteorological predictors on beta concentrations using mixed-effects models. Finally, we imputed missing beta concentrations at RadNet monitors using random forest models for use in future health studies.

Background: Heart Rate Variability (HRV) as a research outcome has the potential for misclassification due to its inability to account for changes in the heart rate. HRV can be parsed into Acceleration Capacity (AC) and Deceleration Capacity (DC) which address these limitations. Objectives: To investigate the associations between AC and DC with short-term and long-term metal PM2.5 exposures; and examine if these associations are mediated by inflammation. Methods: A panel of 45-50 male welders, mean age 39-40 years, had continuous PM2.5 exposure during typical welding work shifts for 4-6 hours repeated 2-5 times over sampling periods in 2010-2012. We also obtained continuous recordings of digital electrocardiograms (ECG) over their work shift using Holter monitors during the same time; and analyzed blood samples before and after each welding shift for potential mediators of inflammation. In our first analysis, we used linear mixed models to assess the association between hourly PM2.5 exposure and each of simultaneously measured hourly AC and DC, controlling for covariates. Then, mediation analysis was done using linear mixed models to assess the associations between shift PM2.5 exposure, potential mediator levels, and AC and DC, controlling for relevant covariates in order to deduce the direct and indirect effects (via the mediator) of PM2.5 on AC and DC. In our final analysis, we used linear regression to assess the association between CEI PM2.5 exposure and each of current AC and DC, controlling for confounders. Results: Negative exposure-response associations were found for AC and DC with increased PM2.5 both in the short-term and long-term exposure after adjusting for covariates. In our mediation models, the proportion of the total effect of PM2.5 on AC or DC (indirect effect) mediated through IL-6 on AC was at best 4%. Conclusions: There are sustained acute and chronic effects of metal particulates on AC and DC even after exposure has ceased. These findings suggest that there may be more pathways that sustain response following exposure other than a direct effect of metal particulates on AC and DC. Furthermore, there may be complex mediating pathways involving interleukin 6.

Background Autism Spectrum Disorder (ASD) is a neurodevelopmental communication disorder with increasing prevalence. Emerging yet conflicting evidence suggests that alterations in the fetal endocrine environment, and specifically in thyroid and androgen signaling, play important roles in the development of the disorder. This question is of high importance, as endocrine problems among women of reproductive-age are relatively common and potentially treatable, and exposures to endocrine-disrupting chemicals are ubiquitous. Better understanding of the involvement of endocrine-related factors in ASD will advance the etiological understanding of the disorder, including the possible contribution of environmental risk factors. To this aim, we evaluated the associations between atypical in-utero thyroid and androgen exposures, and ASD risk. Methods We used a population-based cohort of nearly 500,000 births from a large Israeli health fund, with data abstracted from medical and birth records. Complete validation of all suspected ASD cases was performed. Since androgen levels are not routinely measured clinically, maternal diagnoses of Polycystic Ovarian Syndrome (PCOS) and related conditions, and male newborns’ diagnoses of cryptorchidism and hypospadias, were used as proxy indicators for children presumed to be gestationally exposed to hyper- or hypoandrogenemia, respectively. Associations of ASD risk with maternal thyroid dysfunction were evaluated, and specific effects of gestational thyroid hormone levels were explored. Analyses were performed using generalized estimating equations (GEE) and additive models (GAM), with additional models to assess mediation by androgen-related comorbidities. Results Overall, we observed that children presumed to be exposed to either hyper- or hypo-androgenic in-utero environment had elevated ASD risks. The effect of hyperandrogenemia as indicated by PCOS on ASD risk was largely independent of androgen-related metabolic and cardiovascular comorbidities. The associations with hypoandrogenemia-related male congenital malformations were pregnancy-specific, despite familial aggregation of each disorder individually. Children of mothers with thyroid dysfunction had higher ASD risks, although analyses of gestational thyroid hormone levels suggested that the effects were not directly caused by dysregulation of thyroid hormone concentrations. Conclusions Overall, the results indicate the involvement of endocrine-related factors in ASD etiology, with stronger evidence for androgen hormones. The results additionally suggest that exposure to exogenous factors may drive some of the observed associations.

Across the globe, children living in poverty are disproportionately exposed to environmental and nutritional insults that inhibit proper growth and development. Heavy metals such as lead, arsenic, and manganese are of increasing concern due to the wide range of exposure pathways and their known association with impaired neurodevelopment. Similar in its ubiquity and ability to interfere with proper neurodevelopment, early childhood chronic malnutrition plagues much of the developing world. Though children in poverty experience higher levels of chronic malnutrition and exposure to heavy metals, little is known of the relationship between environmental and nutritional exposures and their combined effects on neurodevelopment. This research provides an in-depth investigation into the relationships between heavy metal exposure, chronic malnutrition and neurodevelopment. We take advantage of data from a prospective birth cohort of mother-child pairs in rural Bangladesh to better understand the effects of single and joint metal exposures and early childhood malnutrition on child growth and neurodevelopment.
This dissertation presents a more complete understanding of the associations between childhood environmental exposures and chronic malnutrition, and the joint effect of these insults on the neurodevelopment of children in Bangladesh.

Hydroelectric reservoir creation accelerates microbial conversion of inorganic mercury (Hg) to bioaccumulative, neurotoxic methylmercury (MeHg). This thesis forecasts MeHg production in flooded reservoirs based on soil organic carbon content and probabilistically models the exposure impacts on local human populations by considering as a case study the Inuit settled downstream from hydroelectric development on the Churchill River, Labrador, Canada. Expected riverine MeHg levels there are approximately ten times present-day average values. Mean MeHg exposures are forecasted to double following flooding and over half of the women of childbearing age and young children in the most northern community are projected to exceed the U.S. EPA’s reference dose. Equal or greater impacts on aqueous MeHg are expected at 11 sites across Canada, suggesting the need for remediation measures prior to flooding or screening of potential sites for human health impacts. Coupled hydrodynamic and biogeochemical simulation of the downstream estuary suggests that estuarine MeHg concentrations increase by 1.2–2.2 times seasonal baseline average. High trophic-level species that contribute most to MeHg exposures are also the basis of indigenous peoples’ traditional diets, contributing disproportionately to intake of polyunsaturated fatty acids and vitamins B12 and D. This analysis supplements traditional food consumption data for Labrador Inuit with publicly available food subsidy records and nutritional databases. While traditional foods account for < 10% of overall calories consumed, they are the main source of MeHg (70%), PCBs (>90%) and a disproportionate source of omega-3 fatty acids (36%) and vitamin D (39%). This analysis calculates the nutritional impacts of substituting higher-MeHg traditional foods with store-bought foods and forecasts health impacts using dose-response functions. Substitution reduces but does not eliminate neurodevelopmental impacts. The relative risk (RR) of cardiovascular mortality is greater for substitution scenarios (population mean RR up to 1.5) than for a baseline diet with MeHg content up to eight times current levels. Substitution generally increase population-wide cancer risks (mean RR up to 1.02) relative to baseline and are associated with a decline in sufficiency of key nutrients (e.g., iron, phosphorus). Dietary advisories alone therefore cannot be used to mitigate risks associated with increased exposures to MeHg.

Statement of Problem: Despite significant advancements in occupational health and safety in recent decades, injury rates in commercial construction remain high. New programs that address the complexity of the construction work environment are needed to keep workers healthy and safe.

Methods: The first step of this dissertation was to explore associations between organizational programs and policies, as measured by a Contractor Safety Assessment Program (CSAP) score, and worker safety climate scores. Next, a safety communication and recognition program was developed and piloted. It was evaluated through a mixed methods approach in a randomized controlled trial. Primary outcome measures included safety climate, awareness, communication, and teambuilding. Additionally, the dynamic nature of the construction site was quantified through an analysis of the determinants of length of stay of construction workers on the worksite.

Results: Correlations between CSAP scores and safety climate scores were weak at best, thus highlighting a gap in communication between management and workers. The B-SAFE program, a safety communication and recognition program was developed to meet this gap. It used data from safety inspection scores to provide feedback to workers on hazards and controls, and provided a reward when the site met a pre-determined safety inspection threshold (a measure that was fair, consistent, attainable and fair). In the final program design, the whole site was treated as the unit of analysis. B-SAFE led to many positive changes, including a statistically significant increase in safety climate scores of 2.29 points (p-value=0.012), when adjusting for time-varying parameters and worker characteristics. Workers at the B-SAFE sites noted increased levels of safety awareness, communication, and teamwork, when compared to control sites. The composition of workers on-site at any given month changed by approximately 50%, and the length of stay on-site was associated with race/ethnicity, union status, title, trade, and musculoskeletal pain (p-values<0.05).

Conclusions: The construction work environment is dynamic, with over half of the population on-site changing each month. This makes applying and evaluating traditional worksite based interventions challenging. Interventions like B-SAFE that are developed to address the complexities can have a positive impact on site safety measures.

Post-influenza bacterial pneumonia is a major cause of morbidity and mortality worldwide. One mechanism for enhanced susceptibility to bacterial infection after influenza is down-regulation of a major phagocytic receptor on alveolar macrophages, macrophage receptor with collagenous structure (MARCO), by interferon- (IFN-), which leads to diminished bacterial clearance. Nrf2, a transcription factor that regulates expression of antioxidant genes, is one of the regulators of MARCO expression. We show that the Nrf2 activator sulforaphane improves MARCO expression and bacterial phagocytosis in alveolar macrophage (AM)-like human monocyte-derived macrophages (HMDMs). It also improves host survival by up-regulating MARCO in a murine model of post-influenza pneumococcal pneumonia. MARCO is spontaneously restored and upregulated in the later phase of influenza virus infection. Initially, elevated IFN levels following influenza infection coincide with attenuated MARCO expression in the lungs. However, as IFN levels returned to normal levels on post-influenza day 11, there was a striking 4.86-fold increase of MARCO expression compared to the low level observed on day 9. To identify regulatory mechanisms underlying this rebound or enhanced post-influenza MARCO expression, we performed RNA sequencing analysis of purified lung macrophages from post-influenza day 9 and 11. Among the differentially expressed genes between post-influenza day 9 and day 11 macrophages were MARCO and Akt. The Akt activator SC79 significantly increased MARCO expression on IFN-treated AM-like HMDMs, whereas the Akt inhibitor perifosine reduced MARCO expression on HMDMs. SC79 treatment significantly improved mouse survival in post-influenza pneumococcal pneumonia. Transcription factor E-box (TFEB) is one of the overrepresented transcription factors binding to candidate genes in our RNA sequencing analysis. SC79-induced MARCO expression in IFN-treated HMDMs was abrogated in TFEB knockdown cells compared to controls. The results suggest that Akt regulates MARCO expression through effects on the transcription factor TFEB. In summary, immunomodulators like Nrf2 activators and Akt activators may promote MARCO expression and host survival in post-influenza bacterial pneumonia, and provide effective preventive and therapeutic strategies against a common and important complication of influenza. Further elucidation of the Akt-TFEB-MARCO pathway may inform therapies to reduce susceptibility to post-influenza bacterial pneumonia.

A research gap in the fields of exposure assessment and toxicology that remains unaddressed is the assimilation of experimental conditions to those of the real world human exposure. Currently, there is a lack of understanding of the properties of particles released by nano-enabled products (NEPs). Thus, we designed a multi-tiered methodology to physico-chemically, morphologically and toxicologically characterize engineered nanomaterials (ENMs) released from NEPs (i.e., toner powder). It is well established that printers emit nanoparticles during their operation; however, the physico-chemical and toxicological characterization of real world printer-emitted nanoparticles (PEPs) remains incomplete, hampering proper risk assessment efforts. For example, a number of studies estimating the potential adverse effects of PEPs used bulk toner particles as test particles rather than the actual particulate matter released by laser printers. Thus, the public health implications of exposure to PEPs remain largely unknown. For this project, a printer exposure generation system suitable for the subsequent physico-chemical, morphological, and toxicological characterization of PEPs was developed and used to assess the properties of particulate matter released from the use of commercially available laser printers. The system consists of a glovebox type environmental chamber for uninterrupted printer operation, real-time and time-integrated particle sampling instrumentation for size fractionation and sampling of PEPs and an exposure chamber for inhalation toxicological studies. Results from our extensive analysis show that laser printers emit up to 1,300,000 particles/cm3, most of which are nanoparticles. Further, we confirmed that a number of ENMs incorporated into toner formulations (e.g., silica, alumina, titania, ceria,) become airborne during printing. Both in vitro and in vivo toxicological evaluation showed PEPs are biologically reactive and may cause significant cytotoxicity, membrane integrity damage, reactive oxygen species production, pro-inflammatory cytokine release, angiogenesis, cytoskeletal and epigenetic changes as well as lung inflammation. This work highlights the importance of understanding life-cycle nano environmental health and safety implications of NEPs and assessing real world exposures and their associated toxicological properties rather than focusing on ‘‘raw’’ materials used in the synthesis of an NEP. Such analysis can be achieved for pollutants emitted by any NEP by employing the multi-tiered methodology described in this dissertation.

The atmosphere is rife with both chemical and physical exposures that may negatively impact the health of those exposed to them. In this dissertation both are explored via the lenses of experiments, exposure assessments, and epidemiology. The first paper is an epidemiological experiment, which examines the impact of both sound intensity levels and frequency composition on biomarkers of stress and cardiovascular activity. The second paper contains a descriptive analysis of the ambient levels of infrasound, low, mid, high, and A-weighted sound levels in a community inundated with major transportation networks. The third paper improves upon the second paper by construction spatial-temporal models of low, mid, high, and A-weighted sound levels in the city of Boston, using an elastic net variable selection approach. Finally, the fourth paper switches gears from physical exposures to chemical exposures. In this paper, models of PAHs—in particular, particle counts and active surface area—in 10 trucking terminals located in the northeast of the United States.

MicroRNAs (miRNAs) mediate inflammation and infection, common manifestations of acute respiratory distress syndrome (ARDS). I proposed to examine whether miRNAs from whole blood serve as potential diagnostic or prognostic biomarkers for ARDS. This nested case-control study (N=530) included 2 cohorts of ARDS patients and critically ill at-risk controls. Whole blood miRNAs were profiled and logistic regression analyses or survival analysis were performed to identify miRNA correlations with ARDS. Receiver operating characteristic (ROC) analysis was used for evaluating miRNA diagnostic performance along with the Lung Injury Prediction Score (LIPS). ARDS patient whole blood miRNA profiling revealed that miR-181a and miR-92a were risk biomarkers of ARDS, whereas miR-424 was a protective biomarker. Addition of these miRNAs increased the risk diagnosis of ARDS from LIPS. We also built a miRNA classifier for predicting ARDS 28-day mortality. In addition, I also did a genome-wide cross trait analysis of 112,000 individuals from UK Biobank to investigate shared genetic architecture of asthma with allergic diseases. Clinical and epidemiological data suggest that asthma and allergic diseases, such as allergic rhinitis and eczema, are associated. One hypothesis to account for the relationship is that these diseases share a common genetic etiology. Heritability has been estimated at high level for asthma and allergic diseases, which suggests that the genetic contribution to them can be significant. We analyzed genome-wide single-nucleotide polymorphism (SNP) data for the asthma and allergic diseases in 35,783 cases and 76,768 controls of European ancestry. We used a logistic regression, linkage disequilibrium score regression, cross trait meta-analysis and GETx tissue enrichment analysis in this study. We have found a strong genetic correlation between asthma and allergic diseases (Rg=0.75, P=6.84×10-62). Cross trait analysis and identified 90 loci. GTEx tissue enrichment analysis showed shared genetic loci between asthma and allergic diseases were enriched in skin and esophageal tissue. Our GWAS study has highlighted shared genetic pathway in immune and inflammatory systems and skin/esophageal tissue by asthma and allergic diseases. This work should support the idea that common patterns of association between asthma and allergy implicate shared biological processes and advance understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.

Some of the major themes that characterize the relationship between the environment and population health in the developing world today include poverty, household access to clean cooking fuel, air pollution, sanitation, and infant/child and maternal health. My dissertation research incorporates some of these themes at the interface of community and household energy in the context of economic development in Ghana. Specifically, my dissertation focuses on features of household energy and poverty in both rural and urban areas, as well as air pollution, and child and maternal health in growing urban areas in what is a data and resource-poor setting of Sub‐Saharan Africa (SSA).

Child mortality is declining in most countries. Very few studies have measured child mortality at fine spatial resolutions, which is relevant for assessing community determinants and interventions. The first paper evaluates subnational inequalities in child mortality and its social and environmental determinants in Ghana by applying Bayesian spatial model to Ghana’s 2000 and 2010 National Population and Housing Censuses in 2000 and 2010. The census data were also used to estimate the distributions of households or persons in each of Ghana’s 110 districts for fuel used for cooking, sanitation facility, drinking water source, and maternal and paternal educations. Median district 5q0 declined from 99 deaths per 1,000 live births in 2000 to 70 in 2010. The decline ranged between <5% in some northern districts, where under-five mortality had been higher in 2000, to >40% in southern districts, where it had been lower in 2000, leading to higher inequalities. Primary education increased in men and women and more households had access to improved water and sanitation and cleaner cooking fuels over the same period. Higher use of liquefied petroleum gas for cooking was associated with lower 5q0 in multivariate analysis. Associations for the other social and environmental variables were not consistent or were weak in the different analyses although there were indications of beneficial effects from replacing wood with charcoal or kerosene, from improved sanitation (but not water), and from higher share of mothers and fathers with primary education.

The second paper examines personal particulate matter exposures and locations of 56 students from eight schools in four neighborhoods in of varying socioeconomic status in Accra, Ghana, using gravimetric and continuous PM2.5 data, with time-matched global positioning system coordinates. Personal PM2.5 exposures ranged from less than 10 μg/m3 to more than 150 μg/m3 (mean 56 μg/m3). Girls had higher exposure than boys (67 vs. 44 μg/m3; p-value = 0.001). Exposure was inversely associated with distance of home or school to main roads, but the associations were not statistically significant in the multivariate model. Use of biomass fuels in the area where the school was located was also associated with higher exposure, as was household’s own biomass use. Paved schoolyard surface was associated with lower exposure. School locations in relation to major roads, materials of school ground surfaces, and biomass use in the area around schools may be important determinants of air pollution exposure.

The third paper assesses the feasibility of using hospital administrative records for understanding air pollution health effects on pregnancy outcomes in Accra. This evaluation addresses whether: (i) the available health administrative data can be used to assess PM pollution-related adverse pregnancy outcomes, in particular birth weight; (ii) the health administrative structure and data can be used in the design of follow-up studies in such settings; (iii) the number of births that occur in the city would provide a large enough sample size; and (iv) birth weight distribution in such complex source-pollution environments varies substantially across neighhorhoods. There are six health districts in the Accra metropolis. In addition to other government and private facilities, each district is served by a Government polyclinic, where maternal and child health records in the district are collated. Neonatal and maternal health records, including anthropometric and demographic information are primarily kept by the individual women in cards provided by the Ghana Health Services. There are an estimated 10,000 births annually in each district. The average birth weight across selected facilities was 3,167±458 g, with individual birth weights ranging from 1,200 g to 6,000 g. Mean birth weight was similar across polyclinics. More than 95% of expectant mothers received at least 4 antenatal care visits at a health facility. Child immunization for the full range of vaccines covers over 80% of children born in the metropolis. A retrospective study of the association of air pollution exposure and birth weight in Accra through the use of hospital administrative records is feasible provided mothers are targeted through the public health units, which is responsible for child immunization.

The objective of this dissertation is to contribute to ongoing research on prenatal metals exposure, in terms of arsenic, lead, and manganese, and infant health and growth, and to deepen the understanding of the complexity of such problems. We seek to do so in three parts. First we examine the association between combined prenatal metals exposure and infant birth weight and head circumference. Then, we look at the effect on birth weight from the HFE gene variants and its interaction effects with arsenic. Finally, we look at the association of prenatal metals exposure and child growth up to 36 months. The study populations of all three of our studies are taken from mothers enrolled in 2 hospitals affiliated with Dhaka Community Hospital in Bangladesh. They were given self-administered questionnaires at time of enrollment and are followed after birth. Child measurements were taken at time of birth, and the biomarker for these studies are cord blood metal measurements. In the first part of this dissertation, through multivariate linear regression, including a metal interaction term, we found that prenatal arsenic and manganese exposure individually associated with lowered birth weight and birth head circumference. We also found evidence of interactions between the two metals, suggesting that joint exposure creates greater deficit in birth outcomes. In the next part, looking at gene-environment interactions, we found significant modification effects of multiple SNPs on the HFE gene that increased the association between arsenic and birth weight. We also found direct effect of less studied HFE genes to lower birth weight. Finally, we assessed the effect of prenatal metals exposure on early growth in children through longitudinal analysis. In following the weight and height of the child from birth up to 36 months of age, our results indicated adverse association between arsenic and manganese on growth.

For more than thirty years, epidemiological and exposure assessment studies have documented the relationship between indoor environmental quality and student health. However, there is an outstanding need to address immediate and long-term building-related environmental challenges. For this reason, this dissertation provides a quantitative evaluation of strategies that could mitigate current harmful indoor exposures and promote investments in healthy environmental quality in schools. It addresses knowledge gaps around a specific set of current strategies across various scales and settings to mitigate indoor environmental exposures including emerging technologies, building and construction policies, and school-related data collection efforts. First, we examined the effectiveness of ‘smart’, dynamic purifiers compared to continuously running purification in a randomized crossover study. We compared changes in indoor particulate matter (PM2.5) and volatile organic compounds (VOCs) concentrations across three intervention arms: no air purification; dynamic purification responsive to elevated PM2.5 and/or VOC concentrations; and continuous purification with fan speed set to half the purifier’s full capability. Both purification types resulted in significant reductions of VOCs, with higher reductions from a continuous system. Dynamic purification can effectively reduce peak exposures to PM2.5 from indoor sources, but continuous purification may better reduce daily PM2.5 and VOC concentrations. Second, using a cross-sectional analysis, we examined the association between school building conditions and chronic absenteeism in Massachusetts. A systematic assessment of public school buildings provided categorical building quality measures across health-related building and site characteristics. Schools with the greatest need for repair were disproportionately attended by disadvantaged and minority students, and associated with high absenteeism. When analyzing specific building systems, schools needing major repairs or replacement of school roofs, building envelope, and site-related features were significantly associated with higher chronic absenteeism compared to schools in need of general maintenance. Addressing building disrepair may provide another strategy for reducing chronic absenteeism. Lastly, in a multi-year study, we characterized building quality at baseline and evaluated school-level associations between acquiring green building certification (Leadership in Energy and Environmental Design and Collaborative for High Performance Schools) and standardized test performance. No association was observed for green buildings because at baseline, future green-certified schools were already higher-performing and the study population of green-certified buildings did not acquire all indoor environmental quality credits available. Allocation of green-certified schools should account for prior academic performance, health, and building quality with greater prioritization of indoor environmental quality credits.