Research Report (Health Effects Institute)[JOURNAL]
Sun
200 papers
Part 4. Interaction between air pollution and respiratory viruses: time-series study of daily mortality and hospital admissions in Hong Kong.
Wong CM, Thach TQ, Chau PY … +10 more , Chan EK, Chung RY, Ou CQ, Yang L, Peiris JS, Thomas GN, Lam TH, Wong TW, Hedley AJ, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Nov · PMID 21446214
BACKGROUND: Populations in Asia are not only at risk of harm to their health through environmental degradation as a result of worsening pollution problems but also constantly threatened by recurring and emerging influenz...
BACKGROUND: Populations in Asia are not only at risk of harm to their health through environmental degradation as a result of worsening pollution problems but also constantly threatened by recurring and emerging influenza epidemics and. pandemics. Situated in the area with the world's fastest growing economy and close to hypothetical epicenters of influenza transmission, Hong Kong offers a special opportunity for testing environmental management and public health surveillance in the region. In the Public Health and Air Pollution in Asia (PAPA*) project, the Hong Kong research team assessed the health effects of air pollution and influenza as well as the interaction between them. The team also assessed disparities in the health effects of air pollution between relatively deprived and more affluent areas in Hong Kong. The aim was to provide answers to outstanding research questions relating to the short-term effects of air pollution on mortality and hospital admissions; the health effects of influenza with a view to validating different measures of influenza activity according to virologic data; the confounding effects of influenza on estimates of the health effects of air pollution; the modifying effects of influenza on the health effects of air pollution; and the modifying effects of neighborhood social deprivation on the health effects of air pollution. DATA: Data on mortality and hospital admissions for all natural causes, as well as the subcategories of cardiovascular diseases (CVD) and respiratory diseases (RD), were derived from the Hong Kong Census and Statistics Department and the Hospital Authority. Daily concentrations of nitrogen dioxide (NO2), sulfur dioxide (SO2), particulate matter with an aerodynamic diameter < or = 10 pm (PM10); and ozone (O3) were derived from eight monitoring stations with hourly data that were at least 75% complete during the study period. Three measures of influenza and respiratory syncytial virus (RSV) activity were derived from positive isolates of specimens in the virology laboratory of Queen Mary Hospital (QMH), the main clinical teaching center at The University of Hong Kong and part of the Hong Kong Hospital Authority network of teaching hospitals: influenza intensity (defined as the weekly proportion of positive isolates of influenza in the total number of specimens received for diagnostic tests); the presence of influenza epidemic (defined as a period when the weekly frequency of these positive isolates is > or = 4% of the annual total number of positive isolates [i.e., twice the expected mean value] in two or more consecutive weeks); and influenza predominance (defined as a period of influenza epidemic when the weekly frequency of RSV was less than 2% for two or more consecutive weeks). The weekly proportion of positive isolates of RSV in total specimens was determined in the same way as for influenza intensity. A social deprivation index (SDI) was defined by taking the average of the proportions of households or persons with the following six characteristics in each geographic area using the census statistics: unemployment; household income < U.S. $250 per month; no schooling at all; never-married status; one-person household; and subtenancy. A Poisson regression with quasi-likelihood to account for overdispersion was used to develop core models for daily health outcomes, with a natural spline smoothing function to filter out seasonal patterns and long-term trends in this time-series study of daily mortality and hospital admissions, and with adjustment for days of the week, temperature, and relative humidity (RH). Air pollutant concentration values were entered into the core model to assess the health effects of specific pollutants. The possible confounding effects of influenza were assessed by observing changes in magnitude of the effect estimate when each influenza measurement was entered into the model; and interactions between air pollution and influenza were assessed by entering the terms for the product of the air pollutant concentration and a measurement of influenza activity into the model. A Poisson regression analysis was performed to assess the effects of air pollution in each area belonging to low, middle, or high social deprivation strata according to the tertiles of the SDI. The differences in air pollution effects were tested by a case-only approach. RESULTS The excess risk (ER) estimates for the short-term effects of air pollution on mortality and hospitalization for broad categories of disease were greater in those 65 years and older than in the all-ages group and were consistent with other studies. The biggest health impacts were seen at the extremes of the age range. The three measures employed for influenza activity based on virologic data-one based on a proportion and the other two using frequencies of positive influenza isolates-were found to produce consistent health impact estimates, in terms of statistical significance. In general, we found that adjustment for influenza activity in air pollution health effect estimations took account of relatively small confounding effects. However, we conclude that it is worthwhile to make the adjustment in a sensitivity analysis and to obtain the best possible range of effect estimates from the data, especially for respiratory hospitalization. Interestingly, interaction effects were found between influenza activity and air pollution in the estimated risks for hospitalization for RD, particularly for 03. These results could be explained in terms of the detrimental effects of both influenza viruses and air pollutants, which may be synergistic or competing with each other, though the mechanism is still unknown. The results deserve further study and the attention of both public health policy makers and virologists in considering prevention strategies. IMPLICATIONS In Hong Kong, where air pollution may pose more of a health threat than in North American and Western European cities, the effects of air pollution also interact with influenza and with residence in socially deprived areas, potentially leading to additional harm. Asian governments should be aware of the combined risks to the health of the population when considering environmental protection and management in the context of economic, urban, and infrastructure development. This is the first study in Asia to examine the interactions between air pollution, influenza, and social deprivation from an epidemiologic perspective. The biologic mechanisms are still unclear, and further research is needed.
Part 3. Estimating the effects of air pollution on mortality in Bangkok, Thailand.
Vichit-Vadakan N, Vajanapoom N, Ostro B … +1 more , HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Nov · PMID 21446213
While the effects of particulate matter (PM*) on mortality have been well documented in North America and Western Europe, considerably less is known about its effects in developing countries in Asia. Existing air polluti...
While the effects of particulate matter (PM*) on mortality have been well documented in North America and Western Europe, considerably less is known about its effects in developing countries in Asia. Existing air pollution data in Bangkok, Thailand, indicate that airborne concentrations of PM < or = 10 pm in aerodynamic diameter (PM10) are as high or higher than those experienced in most cities in North America and Western Europe. At the same time, the demographics, activity patterns, and background health status of the population, as well as the chemical composition of PM, are different in Bangkok. It is important, therefore, to determine whether the effects of PM10 on mortality occurring in this large metropolitan area are similar to those in Western cities. The quality and completeness of Bangkok mortality data have been recently enhanced by the completion of a few mortality studies and through input from monitors currently measuring daily PM10 in Bangkok. In this analysis, we examined the effects of PM10 and several gaseous pollutants on daily mortality for the years 1999 through 2003. Our results suggest strong associations between several different mortality outcomes and levels of PM10 and several of the gaseous pollutants, including nitrogen dioxide (NO2), nitric oxide (NO), and ozone (O3). In many cases, the effect estimates were higher than the approximately 6% per 10 microg/m3 typically reported in Western industrialized nations-based on reviews by the U.S. Environmental Protection Agency (U.S. EPA) and the World Health Organization (WHO) (Anderson et al. 2004). For example, the excess risk (ER) for mortality due to all natural causes was 1.3% (95% confidence interval [CI], 0.8 to 1.7), with higher ERs for cardiovascular and respiratory mortality of 1.9% (95% CI, 0.8 to 3.0) and 1.0% (95% CI, -0.4 to 2.4), respectively. Of particular note, for this warm, tropical city of approximately 6 to 10 million people, is that there is no covariation between pollution and cold weather, with its associated adverse health problems. Multiday averages of PM10 generated even higher effect estimates. Our analysis of age- and disease-specific mortality indicated elevated ERs for young children, especially infants with respiratory illnesses, children less than 5 years of age with lower respiratory infections (LRIs), and people with asthma. Age-restricted analyses showed that the associations between mortality due to all natural causes and PM10 concentration increased with age, with the strongest effects among people aged 75 years and older. However, associations between increases in PM10 concentration and mortality were observed for all of the other age groups. With a few exceptions, relatively similar results were observed for several of the other pollutants-sulfur dioxide (SO2), NO2, O3, and NO, which were highly correlated with PM10. However, many of the effects from gaseous pollutants were attenuated in multipollutant models, while effects from PM10 appeared to be most consistent. In addition, there was some evidence of an independent effect of O3 for certain health outcomes. We conducted substantial sensitivity analyses to examine whether our results were robust. The results indicated that our core model was generally robust to the choice of model specification, spline model, degrees of freedom (df) of time-smoothing functions, lags for temperature, adjustment for autocorrelation, adjustment for epidemics, and adjustment for missing values using centered data (see the description of the centering method used in the Common Protocol found at the end of this volume). Finally, the concentration-response functions for most of the pollutants appear to be linear. Thus, our sensitivity analyses results suggest an impact of pollution on mortality in Bangkok that is fairly consistent. They also provide support for the extrapolation of results from health effects studies conducted in North America and Western Europe to other parts of the world, including developing countries in Asia.
Part 2. Association of daily mortality with ambient air pollution, and effect modification by extremely high temperature in Wuhan, China.
Qian Z, He Q, Lin HM … +16 more , Kong L, Zhou D, Liang S, Zhu Z, Liao D, Liu W, Bentley CM, Dan J, Wang B, Yang N, Xu S, Gong J, Wei H, Sun H, Qin Z, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Nov · PMID 21446212
Fewer studies have been published on the association between daily mortality and ambient air pollution in Asia than in the United States and Europe. This study was undertaken in Wuhan, China, to investigate the acute eff...
Fewer studies have been published on the association between daily mortality and ambient air pollution in Asia than in the United States and Europe. This study was undertaken in Wuhan, China, to investigate the acute effects of air pollution on mortality with an emphasis on particulate matter (PM*). There were three primary aims: (1) to examine the associations of daily mortality due to all natural causes and daily cause-specific mortality (cardiovascular [CVD], stroke, cardiac [CARD], respiratory [RD], cardiopulmonary [CP], and non-cardiopulmonary [non-CP] causes) with daily mean concentrations (microg/m3) of PM with an aerodynamic diameter--10 pm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), or ozone (O3); (2) to investigate the effect modification of extremely high temperature on the association between air pollution and daily mortality due to all natural causes and daily cause-specific mortality; and (3) to assess the uncertainty of effect estimates caused by the change in International Classification of Disease (ICD) coding of mortality data from Revision 9 (ICD-9) to Revision 10 (ICD-10) code. Wuhan is called an "oven city" in China because of its extremely hot summers (the average daily temperature in July is 37.2 degrees C and maximum daily temperature often exceeds 40 degrees C). Approximately 4.5 million residents live in the core city area of 201 km2, where air pollution levels are higher and ranges are wider than the levels in most cities studied in the published literature. We obtained daily mean levels of PM10, SO2, and NO2 concentrations from five fixed-site air monitoring stations operated by the Wuhan Environmental Monitoring Center (WEMC). O3 data were obtained from two stations, and 8-hour averages, from 10:00 to 18:00, were used. Daily mortality data were obtained from the Wuhan Centres for Disease Prevention and Control (WCDC) during the study period of July 1, 2000, to June 30, 2004. To achieve the first aim, we used a regression of the logarithm of daily counts of mortality due to all natural causes and cause-specific mortality on the daily mean concentrations of the four pollutants while controlling for weather, temporal factors, and other important covariates with generalized additive models (GAMs). We derived pollutant effect estimations for 0-day, 1-day, 2-day, 3-day, and 4-day lagged exposure levels, and the averages of 0-day and 1-day lags (lag 0-1 day) and of 0-day, 1-day, 2-day, and 3-day lags (lag 0-3 days) before the event of death. In addition, we used individual-level data (e.g., age and sex) to classify subgroups in stratified analyses. Furthermore, we explored the nonlinear shapes ("thresholds") of the exposure-response relations. To achieve the second aim, we tested the hypothesis that extremely high temperature modifies the associations between air pollution and daily mortality. We developed three corresponding weather indicators: "extremely hot," "extremely cold," and "normal temperatures." The estimates were obtained from the models for the main effects and for the pollutant-temperature interaction for each pollutant and each cause of mortality. To achieve the third aim, we conducted an additional analysis. We examined the concordance rates and kappa statistics between the ICD-9-coded mortality data and the ICD-10-coded mortality data for the year 2002. We also compared the magnitudes of the estimated effects resulting from the use of the two types of ICD-coded mortality data. In general, the largest pollutant effects were observed at lag 0-1 day. Therefore, for this report, we focused on the results obtained from the lag 0-1 models. We observed consistent associations between PM10 and mortality: every 10-microg/m3 increase in PM10 daily concentration at lag 0-1 day produced a statistically significant association with an increase in mortality due to all natural causes (0.43%; 95% confidence interval [CI], 0.24 to 0.62), CVD (0.57%; 95% CI, 0.31 to 0.84), stroke (0.57%; 95% CI, 0.25 to 0.88), CARD (0.49%; 95% CI, 0.04 to 0.94), RD (0.87%; 95% CI, 0.34 to 1.41), CP (0.52%; 95% CI, 0.27 to 0.77), and non-CP (0.30%; 95% CI, 0.05 to 0.54). In general, these effects were stronger in females than in males and were also stronger among the elderly (> or = 65 years) than among the young. The results of sensitivity testing over the range of exposures from 24.8 to 477.8 microg/m3 also suggest the appropriateness of assuming a linear relation between daily mortality and PM10. Among the gaseous pollutants, we also observed statistically significant associations of mortality with NO, and SO2, and that the estimated effects of these two pollutants were stronger than the PM10 effects. The patterns of NO2 and SO2 associations were similar to those of PM10 in terms of sex, age, and linearity. O3 was not associated with mortality. In the analysis of the effect modification of extremely high temperature on the association between air pollution and daily mortality, only the interaction of PM10 with temperature was statistically significant. Specifically, the interaction terms were statistically significant for mortality due to all natural (P = 0.014), CVD (P = 0.007), and CP (P = 0.014) causes. Across the three temperature groups, the strongest PM10 effects occurred mainly on days with extremely high temperatures for mortality due to all natural (2.20%; 95% CI, 0.74 to 3.68), CVD (3.28%; 95% CI, 1.24 to 5.37), and CP (3.02%; 95% CI, 1.03 to 5.04) causes. The weakest effects occurred at normal temperature days, with the effects on days with low temperatures in the middle. To assess the uncertainty of the effect estimates caused by the change from ICD-9-coded mortality data to ICD-10-coded mortality data, we compared the two sets of data and found high concordance rates (> 99.3%) and kappa statistics close to 1.0 (> 0.98). All effect estimates showed very little change. All statistically significant levels of the estimated effects remained unchanged. In conclusion, the findings for the aims from the current study are consistent with those in most previous studies of air pollution and mortality. The small differences between mortality effects for deaths coded using ICD-9 and ICD-10 show that the change in coding had a minimal impact on our study. Few published papers have reported synergistic effects of extremely high temperatures and air pollution on mortality, and further studies are needed. Establishing causal links between heat, PM10, and mortality will require further toxicologic and cohort studies.
Part 1. A time-series study of ambient air pollution and daily mortality in Shanghai, China.
Kan H, Chen B, Zhao N … +6 more , London SJ, Song G, Chen G, Zhang Y, Jiang L, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Nov · PMID 21446211
Although the relation between outdoor air pollution and daily mortality has been examined in several Chinese cities, there are still a number of key scientific issues to be addressed concerning the health effects of air...
Although the relation between outdoor air pollution and daily mortality has been examined in several Chinese cities, there are still a number of key scientific issues to be addressed concerning the health effects of air pollution in China. Given the changes over the past decade in concentrations and sources of air pollution (e.g., the change from one predominant source [coal combustion], which was typical of the twentieth century, to a mix of sources [coal combustion and motor-vehicle emissions]) and transition in China, it is worthwhile to investigate the acute effects of outdoor air pollution on mortality outcomes in the country. We conducted a time-series study to investigate the relation between outdoor air pollution and daily mortality in Shanghai using four years of daily data (2001-2004). This study is a part of the Public Health and Air Pollution in Asia (PAPA) program supported by the Health Effects Institute (HEI). We collected data on daily mortality, air pollution, and weather from the Shanghai Municipal Center of Disease Control and Prevention (SMCDCP), Shanghai Environmental Monitoring Center, and Shanghai Meteorologic Bureau. An independent auditing team assigned by HEI validated all the data. Our statistical analysis followed the Common Protocol of the PAPA program (found at the end of this volume). Briefly, a natural-spline model was used to analyze the mortality, air pollution, and covariate data. We first constructed the basic models for various mortality outcomes excluding variables for air pollution, and used the partial autocorrelation function of the residuals to guide the selection of degrees of freedom for time trend and lag days for the autoregression terms. Thereafter, we introduced the pollutant variables and analyzed their effects on mortality outcomes, including both mortality due to all natural (nonaccidental) causes and cause-specific mortality. We fitted single- and multipollutant models to assess the stability of the effects of the pollutants. For mortality due to all natural causes, we also examined the associations stratified by sex and age. Stratified analyses by education level, used as a measure of socioeconomic status, were conducted as well. In addition to an analysis of the entire study period, the effects of air pollution in just the warm season (from April to September) and cool season (from October to March) were analyzed. We also examined the effects of alternative model specifications--such as lag effects of pollutants and temperature, degrees of freedom for time trend and weather conditions, statistical approaches, and averaging methods for pollutant concentrations-on the estimated effects of air pollution. We found significant associations between the air pollutants--particulate matter 10 pm or less in aerodynamic diameter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) -and daily mortality from all natural causes and from cardiopulmonary diseases. The increased mortality risks found in the data from Shanghai were generally similar in magnitude, per concentration of pollutant, to the risks found in research from other parts of the world. An increase of 10 microg/m3 in 2-day moving average concentrations of PM10, SO2, NO2, and O3 corresponded to 0.26% (95% confidence interval [CI], 0.14-0.37), 0.95% (95% CI, 0.62-1.28), 0.97% (95% CI, 0.66-1.27), and 0.31% (95% CI, 0.04-0.58) increases, respectively, in mortality due to all natural causes. Sensitivity analyses suggested that our findings were generally insensitive to alternative model specifications. We found significant effects of the gaseous pollutants SO2 and NO2 on daily mortality after adjustment for PM10. Our analysis also provided preliminary, but not conclusive, evidence that women, older people, and people with a low level of education might be more vulnerable to air pollution than men, younger people, and people with a high level of education. In addition, the associations between air pollution and daily mortality appeared to be more pronounced in the cool season than in the warm. We concluded that short-term exposure to outdoor air pollution (PM10, SO2, NO2, and O3) was associated with daily mortality in Shanghai and that gaseous pollutants might have independent health effects in the city. Overall, the results of the study appeared largely consistent with those reported in other locations worldwide. Further research will be needed to disentangle the effects of the various pollutants and to gain more conclusive insights into the influence of various sociodemographic characteristics (e.g., sex, age, and socioeconomic status) and of season on the associations between air pollution and daily mortality.
Improved source apportionment and speciation of low-volume particulate matter samples.
Schauer JJ, Majestic BJ, Sheesley RJ … +4 more , Shafer MM, Deminter JT, Mieritz M, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Dec · PMID 21409950
New chemical analysis methods for the characterization of atmospheric particulate matter (PM)* samples were developed and demonstrated in order to expand the number of such methods for use in future health studies involv...
New chemical analysis methods for the characterization of atmospheric particulate matter (PM)* samples were developed and demonstrated in order to expand the number of such methods for use in future health studies involving PM. Three sets of methods were, developed, for the analysis (1) of organic tracer compounds in low-volume personal exposure samples (for source apportionment), (2) of trace metals and other trace elements in low-volume personal exposure samples, and (3) of the speciation of the oxidation states of water-soluble iron (Fe), manganese (Mn), and chromium (Cr) in PM samples. The development of the second set of methods built on previous work by the project team, which had in the past used similar methods in atmospheric source apportionment studies. The principal challenges in adapting these methods to the analysis of personal exposure samples were the improvement of detection limits (DLs) and control of the low-level contamination that can compromise personal exposure samples. A secondary goal of our development efforts was to reduce the cost and complexity of the three sets of methods in order to help facilitate their broader use in future health studies. The goals of the project were achieved, and the ability to integrate the methods into existing health studies was demonstrated by way of conducting two pilot studies. The first study involved analysis of trace elements in size-resolved PM samples that had been collected to represent study subjects' personal exposures along with simultaneous measures of indoor and outdoor PM concentrations. The second study involved analysis of the speciation of organic tracer compounds in personal exposure samples, indoor samples, and outdoor samples in order to understand the diesel PM exposure of study subjects in various job classifications in an occupational setting. Both pilot studies used existing samples from. large multi-year health studies and were intended to demonstrate the feasibility and value of using the new chemical analysis methods to better characterize the personal exposure samples. Analysis of the health data and the broader implications of the exposure assessments were not evaluated as part of the present study, but our pilot-study measurements are expected to contribute to investigators' future analyses in the large multi-year health studies. The methods we developed for the low-cost measurement of the oxidation states of Fe, Mn, and Cr in atmospheric PM samples are extremely sensitive and well suited for use in health studies. To demonstrate the utility of these methods, small-scale studies were conducted to characterize the redox cycling of Fe in PM on the time scale of atmospheric transport from source to personal exposure and to provide preliminary data on the atmospheric concentrations of soluble forms of the target metals in selected urban environments (in order to help focus future research seeking to understand the role of metals in human exposure to PM and its adverse health effects). The present report summarizes the methods that were developed and demonstrated to be suitable for use in health studies and provides pilot-scale data that can be used to develop hypotheses and experimental strategies to further enhance the ability of future health studies to elucidate the role of PM, PM sources, and PM components in the observed associations between atmospheric PM and adverse human health outcomes.
Evaluating heterogeneity in indoor and outdoor air pollution using land-use regression and constrained factor analysis.
Levy JI, Clougherty JE, Baxter LK … +3 more , Houseman EA, Paciorek CJ, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Dec · PMID 21409949
Previous studies have identified associations between traffic exposures and a variety of adverse health effects, but many of these studies relied on proximity measures rather than measured or modeled concentrations of sp...
Previous studies have identified associations between traffic exposures and a variety of adverse health effects, but many of these studies relied on proximity measures rather than measured or modeled concentrations of specific air pollutants, complicating interpretability of the findings. An increasing number of studies have used land-use regression (LUR) or other techniques to model small-scale variability in concentrations of specific air pollutants. However, these studies have generally considered a limited number of pollutants, focused on outdoor concentrations (or indoor concentrations of ambient origin) when indoor concentrations are better proxies for personal exposures, and have not taken full advantage of statistical methods for source apportionment that may have provided insight about the structure of the LUR models and the interpretability of model results. Given these issues, the primary objective of our study was to determine predictors of indoor and outdoor residential concentrations of multiple traffic-related air pollutants within an urban area, based on a combination of central site monitoring data; geographic information system (GIS) covariates reflecting traffic and other outdoor sources; questionnaire data reflecting indoor sources and activities that affect ventilation rates; and factor-analytic methods to better infer source contributions. As part of a prospective birth cohort study assessing asthma etiology in urban Boston, we collected indoor and/or outdoor 3-to-4 day samples of nitrogen dioxide (NO2) and fine particulate matter with an aerodynamic diameter or = 2.5 pm (PM2.5) at 44 residences during multiple seasons of the year from 2003 through 2005. We performed reflectance analysis, x-ray fluorescence spectroscopy (XRF), and high-resolution inductively coupled plasma-mass spectrometry (ICP-MS) on particle filters to estimate the concentrations of elemental carbon (EC), trace elements, and water-soluble metals, respectively. We derived multiple indicators of traffic using Massachusetts Highway Department (MHD) data and traffic counts collected outside the residences where the air monitoring was conducted. We used a standardized questionnaire to collect data on home characteristics and occupant behaviors. Additional housing information was collected through property tax records. Ambient concentrations of pollutants as well as meteorological data were collected from centrally located ambient monitors. We used GIS-based LUR models to explain spatial and temporal variability in residential outdoor concentrations of PM2.5, EC, and NO2. We subsequently derived latent-source factors for residential outdoor concentrations using confirmatory factor analysis constrained to nonnegative loadings. We developed LUR models to determine whether GIS covariates and other predictors explain factor variability and thereby support initial factor interpretations. To evaluate indoor concentrations, we developed physically interpretable regression models that explored the relationship between measured indoor and outdoor concentrations, relying on questionnaire data to characterize indoor sources and activities. Because outdoor pollutant concentrations measured directly outside of homes are unlikely to be available for most large epidemiologic studies, we developed regression models to explain indoor concentrations of PM2.5, EC, and NO2 as a function of other, more readily available data: GIS covariates, questionnaire data reflecting both sources and ventilation, and central site monitoring data. As we did for outdoor concentrations, we then derived latent-source factors for residential indoor concentrations and developed regression models explaining variability in these indoor latent-source factors. Finally, to provide insight about the effects of improved characterization of exposures for the results of subsequent epidemiologic investigations, we developed a simulation framework to quantitatively compare the implications of using exposure models derived from validation studies with the use of other surrogate models with varying amounts of measurement error. The concentrations of outdoor PM2.5 were strongly associated with the central site monitor data, whereas EC concentrations showed greater spatial variability, especially during colder months, and were predicted by the length of roadway within 200 m of the home. Outdoor NO2 also showed significant spatial variability, predicted in part by population density and roadway length within 50 m of the home. Our constrained factor analysis of outdoor concentrations produced loadings indicating long-range transport, brake wear and traffic exhaust, diesel exhaust, fuel oil combustion, and resuspended road dust as sources; corresponding LUR models largely corroborated these factor interpretations through covariate significance. For example, long-range transport was predicted by central site PM2.5, and season, brake wear and traffic exhaust and resuspended road dust by traffic and residential density, diesel exhaust by the percentage of diesel traffic on the nearest major road, and fuel oil combustion by population density. Our modeling of the concentrations of indoor pollutants demonstrated substantial variability in indoor-outdoor relationships across constituents, helping to separate constituents dominated by outdoor sources (e.g., S, Se, and V) from those dominated by indoor sources (e.g., Ca and Si). Regression models indicated that indoor PM2.5 was not influenced substantially by local traffic but had significant indoor sources (cooking activity and occupant density), while EC was associated with distance to the nearest designated truck route, and NO2 was associated with both traffic density within 50 m of the home and gas stove usage. Our constrained factor analysis of indoor concentrations helped to separate outdoor-dominated factors from indoor-dominated factors, though some factors appeared to be influenced by both indoor and outdoor sources. Subsequent factor analyses of the indoor-attributable fractions from indoor-outdoor regression models provided generally consistent interpretations of indoor-dominated factors. The use of regression models on indoor factors demonstrated the limited predictive power of questionnaire data related to indoor sources, but reinforced the viability of modeling indoor concentrations of pollutants of ambient origin. In spite of the relatively weak predictive power of some of the indoor-concentration regression models, our epidemiologic simulations illustrated that exposure models with fairly modest R2 values (in the range of 0.3 through 0.4, corresponding with the regression models for PM2.5 and NO2) yielded substantial improvements in epidemiologic study performance relative to the use of exposure proxies that could be applied in the absence of validation studies. In spite of limitations related to sample size and available covariate data, our study demonstrated significant outdoor spatial variability within an urban area in NO2 and in several constituents of airborne particles. LUR techniques combined with constrained factor analysis helped to disentangle the contributions to temporal variability of local, long-range transport, and other sources, ultimately allowing exposures from defined source categories to be investigated in epidemiologic studies. For the indoor residential environment, we demonstrated substantial variability in indoor-outdoor relationships among particle constituents; then, using information from public databases and focused questionnaire data, we were able to predict indoor concentrations for a subset of key pollutants. Constrained factor analysis methods applied to the indoor environment helped to separate indoor sources from outdoor sources. The corresponding indoor regression models had limited predictive power, reinforcing the complexity of characterizing the indoor environment when only limited information about key predictors is available. This finding also underscores the likelihood that these regression models might characterize indoor concentrations of pollutants with ambient origins better than they can the indoor concentrations from all sources. Our findings provide direction for future studies characterizing indoor exposure sources and patterns, and our epidemiologic simulation reinforced the importance of reducing measurement error in a context where many traffic-related air pollutants are influenced by both indoor and outdoor sources. The combination of analytical techniques used in our study could ultimately allow for more refined exposure characterization and evaluation of the relative contributions of various sources to health outcomes in epidemiologic studies.
Pulmonary effects of inhaled diesel exhaust in young and old mice: a pilot project.
Laskin DL, Mainelis G, Turpin BJ … +3 more , Patel KJ, Sunil VR, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Sep · PMID 21381634
It is well established that exposure to ambient fine particulate matter (PM), defined as PM < or = 2.5 microm in aerodynamic diameter (PM2.5), is associated with increased cardiovascular morbidity and mortality and that...
It is well established that exposure to ambient fine particulate matter (PM), defined as PM < or = 2.5 microm in aerodynamic diameter (PM2.5), is associated with increased cardiovascular morbidity and mortality and that elderly persons are particularly susceptible to these effects. We speculated that the increased susceptibility of elderly persons to PM is due to altered production of inflammatory mediators and antioxidants in the lung. We performed pilot studies in an animal model to test this hypothesis. For these studies we used diesel exhaust (DE), a major component of urban PM, as a model. Two groups of male CB6F1 mice, 2 months and 18 months old, (referred to in this report as young and old mice, respectively) were exposed to DE at 300 or 1000 microg/m3 PM (referred to as low- or high-dose DE, respectively), or to filtered air as a control, for one 3-hour period (single exposure) or for 3 hours on each of three consecutive days (repeated exposure). Mice were killed and bronchoalveolar lavage (BAL) fluid, serum, and lung tissue were collected immediately after exposure (0 hours) and 24 hours after the final exposure. After single or repeated exposure to DE, persistent structural alterations and inflammation were observed in the lungs of old mice. These changes consisted of patchy thickening of alveolar septa and an increase in the number of neutrophils and macrophages in alveolar spaces. In the young mice, in contrast, no major alterations in lung histology were noted. In old but not in young mice, significant increases in messenger RNA (mRNA) expression of the oxidative-stress marker lipocalin 24p3 were also observed. In both young and old mice, exposure to DE was associated with increased expression of tumor necrosis factor alpha (TNF-alpha) mRNA in the lung. However, this response was attenuated in old mice. Exposure to high-dose DE resulted in significant increases in interleukin (IL)-6 and IL-8 mRNA expression in the lungs of old animals; these increases persisted for 24 hours. Whereas IL-6 was also up-regulated in young mice after DE exposure, no major effects were evident on the expression of IL-8 mRNA. Expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) was decreased in lung tissue from young animals after single or repeated exposure to DE. In contrast, constitutive expression of MnSOD was not evident in lungs of old mice, and DE had no effect on the expression of this antioxidant. These preliminary data confirm that old mice are more sensitive to DE than young mice and that increased sensitivity is associated with altered expression of inflammatory cytokines and the antioxidant MnSOD. These aberrations may contribute to the increased susceptibility of old mice to inhaled PM.
Mutagenicity of stereochemical configurations of 1,3-butadiene epoxy metabolites in human cells.
Meng RQ, Hackfeld LC, Hedge RP … +4 more , Wisse LA, Redetzke DL, Walker VE, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Jun · PMID 20853577
The mutagenic and carcinogenic effects of 1,3-butadiene (BD*) are related to its bioactivation to several DNA-reactive metabolites, including 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-...
The mutagenic and carcinogenic effects of 1,3-butadiene (BD*) are related to its bioactivation to several DNA-reactive metabolites, including 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol). Accumulated evidence indicates that stereochemical configurations of BD metabolites may play a role in the mutagenic and carcinogenic action of BD. The objective of this study was to evaluate the cytotoxicity and mutagenicity of each stereoisomer of major BD metabolites in human cells. For this purpose, nine stereochemical forms of BDO, BDO2, and BDO-diol were synthesized. TK6 cells, a human lymphoblastoid cell line, were exposed to each stereoisomer. Cytotoxicity was measured by comparing cloning efficiencies (CEs) in chemical-exposed cells versus those in control cells. Based on the results of cytotoxicity tests, TK6 cells were exposed to 0; 2, 4, or 6 pM of each form of BDO2, or to 0, 200, 400, or 600 pMof each form of BDO for 24 hours to determine the mutagenic efficiencies. The exposure concentrations for BDO-diol ranged from 5 to 1000 pM. The mutagenicity was measured by determining, in a lymphocyte cloning assay, the mutant frequencies (Mfs) in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) genes. HPRT mutants collected from cells exposed to the three forms of BDO2 were analyzed by polymerase chain reaction (PCR) to characterize large genetic alterations. All three stereoisomers of BDO2 [(2R,3R)-BDO2, (2S,3S)-BDO2, and meso-BDO2] caused increased HPRT and TK Mfs compared with the concurrent control samples, with P values ranged from 0.05 to 0.001. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of BDO2. Molecular analysis ofHPRTmutants revealed similar distributions of deletion mutations caused by the three isomers of BDO2. There were also no statistical differences in mutagenic efficiencies between the two isomers of BDO [(2R)-BDO and (2S)-BDO] in TK6 cells. These results were consistent with the in vivo finding that there was little difference in the mutagenic efficiencies of (+)-BDO2 versus meso-BDO2 in rodents. Thus, in terms of mutagenic potency, there was no evidence that stereochemical configurations of BDO and BDO2 play a significant role in the mutagenicity and carcinogenicity of BD. The most significant results of this study were the marked differences in cytotoxicity and mutagenicity among the four stereoisomers of BDO-diol [(2R,3R)-BDO-diol, (2R,3S)-BDO-diol, (2S,3R)-BDO-diol, and (2S,3S)-BDO-diol]. (2R,3S)-BDO-diol was at least 30-fold more cytotoxic and mutagenic than the other three forms of BDO-diol. This was consistent with the finding that 75% of the adduct N7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) originated from (2R,3S)-BDO-diol in the lungs of mice exposed to BD. The mutagenic potency of (2R,3S)-BDO-diol was much closer to that of BDO2 than previously demonstrated in experiments in which stereochemistry was not considered. The current study demonstrated that the mutagenic potency of (2R,3S)-BDO-diol was only 5-to-l0-fold less than the average equimolar effect of BDO2 stereoisomers in the HPRT and TK genes, and was 10-to-20-fold greater than the average equimolar effect of BDO stereoisomers in the HPRT and TKgenes. Previous DNA and hemoglobin adduct data demonstrated that BDO-diol is the dominant BD metabolite available to react with macromolecules in vivo after BD exposure (Pérez et al. 1997; Swenberg et al. 2001). Thus, the differences in BD carcinogenesis among rodent species may be significantly accounted for by the stereochemistry-dependent distributions of BDO-diol metabolites and BDO-diol-DNA adducts, and by the mutagenic efficiencies of BDO-diol in mice and rats.
Development and application of a sensitive method to determine concentrations of acrolein and other carbonyls in ambient air.
Cahill TM, Charles MJ, Seaman VY … +1 more , HEI Health Review Committee
Res Rep Health Eff Inst · 2010 May · PMID 20608023
Acrolein, an unsaturated aldehyde, has been identified as one of the most important toxic air pollutants in recent assessments of ambient air quality. Current methods for determining acrolein concentrations, however, suf...
Acrolein, an unsaturated aldehyde, has been identified as one of the most important toxic air pollutants in recent assessments of ambient air quality. Current methods for determining acrolein concentrations, however, suffer from poor sensitivity, selectivity, and reproducibility. The collection and analysis of unsaturated carbonyls, and acrolein in particular, is complicated by unstable derivatives, coelution of similar compounds, and ozone interference. The primary objective of this research was to develop an analytical method to measure acrolein and other volatile carbonyls present in low part-per-trillion concentrations in ambient air samples obtained over short sampling periods. The method we devised uses a mist chamber in which carbonyls from air samples form water-soluble adducts with bisulfite in the chamber solution, effectively trapping the carbonyls in the solution. The mist chamber methodology proved effective, with collection efficiency for acrolein of at least 70% for each mist chamber at a flow rate of approximately 17 L/min. After the sample collection, the carbonyls are liberated from the bisulfite adducts through the addition of hydrogen peroxide, which converts the bisulfite to sulfate, reversing the bisulfite addition reaction. The free carbonyls are then derivatized by o-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA*), which stabilizes the analytes and makes them easier to detect by electron-capture negative ionization mass spectrometry (ECNI-MS). The derivatives are then extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). The mist chamber method was applied in a field test to determine the extent of acrolein in ambient air near the Peace Bridge plaza in Buffalo, New York, an area of heavy traffic near a major border crossing between the United States and Canada. In addition, XAD-2 adsorbent cartridges coated with 2-(hydroxymethyl)piperidine (2-HMP) according to Occupational Safety and Health Administration (OSHA) Method 52 and passive samplers based on the use of dansylhydrazine (DNSH) were deployed at this location at the same time, which provided the opportunity to compare methods. The mist chamber results showed that the Peace Bridge traffic was clearly a source of acrolein, with an average concentration of 0.26 microg/m3 at a site 152.4 m downwind (northeast) of the plaza. The OSHA cartridges proved to be too insensitive to determine ambient acrolein concentrations. The DNSH passive samplers returned concentrations near the limit of detection; hence the values were a little higher and less consistent than those in the mist chamber results. The optimized mist chamber method was then applied to determine atmospheric acrolein concentrations at three sites in northern California: a site chosen to reflect the hemispheric background, a region dominated by biogenic sources, and an urban environment. The resulting average acrolein concentrations were 0.056, 0.089, and 0.290 microg/m3, respectively, and the limit of detection was 0.012 microg/m3 The consistency of the replicate samples obtained in the field was good, with the relative standard deviations (RSDs) ranging from 19% at the hemispheric background site to 3% at the urban site. The advantage of the current mist chamber method is that it can determine ambient acrolein concentrations over short time periods with enough sensitivity to be effective even in relatively "clean" environments. This allows for the determination of temporal patterns related to acrolein concentrations, such as diurnal cycles of reaction kinetics. The main disadvantages of the method are that it is laborious and time-consuming and requires specialized equipment that makes it difficult to utilize for routine monitoring of acrolein.
Impact of improved air quality during the 1996 Summer Olympic Games in Atlanta on multiple cardiovascular and respiratory outcomes.
Peel JL, Klein M, Flanders WD … +3 more , Mulholland JA, Tolbert PE, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Apr · PMID 20575278
Substantial evidence supports an association between ambient air pollution, especially particulate matter (PM*) and ozone (O3), and acute cardiovascular and respiratory morbidity. There is increasing interest in accounta...
Substantial evidence supports an association between ambient air pollution, especially particulate matter (PM*) and ozone (O3), and acute cardiovascular and respiratory morbidity. There is increasing interest in accountability research to evaluate whether actions taken to reduce air pollution will result in reduced morbidity. This study capitalized on a unique opportunity to evaluate the impact of a local, short-term intervention effort to reduce traffic in Atlanta during the 1996 Summer Olympic Games (July 19-August 4). Air pollutant concentrations both inside and outside of Atlanta were examined during the Olympic period and surrounding periods. Emergency department (ED) visits were examined to evaluate changes in usage patterns. ED visits for respiratory and cardiovascular conditions were examined in relation to the Olympic period using Poisson time-series analysis with adjustment for time trends and meteorologic conditions. O3 concentrations were approximately 30% lower during the Olympic Games compared with the four weeks before and after the Olympic Games (baseline periods); however, we observed similar reductions in O3 concentrations in several other cities in the Southeastern United States. We observed little or no evidence of reduced ED visits during the Olympic Games; the estimates were sensitive to choice of analytic model and to method of adjusting for temporal trends. The meteorologic conditions during the Olympic Games, along with the reductions in O3 observed in various cities not impacted by the Olympic Games, suggest that both meteorologic conditions-and reduced traffic may have played a role in the observed reduction in O3 concentration in Atlanta. Additionally, it is likely that this particular intervention strategy would not be sustainable as a pollution-reduction strategy. This study demonstrates some limitations of conducting retrospective accountability research.
Atmospheric transformation of diesel emissions.
Zielinska B, Samy S, McDonald JD … +2 more , Seagrave J, HEI Health Review Committee
Res Rep Health Eff Inst · 2010 Apr · PMID 20572366
The hypothesis of this study was that exposing diesel exhaust (DE*) to the atmosphere transforms its composition and toxicity. Our specific aims were (1) to characterize the gas- and particle-phase products of atmospheri...
The hypothesis of this study was that exposing diesel exhaust (DE*) to the atmosphere transforms its composition and toxicity. Our specific aims were (1) to characterize the gas- and particle-phase products of atmospheric transformations of DE under the influence of daylight, ozone (O3), hydroxyl (OH) radicals, and nitrate (NO3) radicals; and (2) to explore the biologic activity of DE before and after the transformations took place. The study was executed with the aid of the EUPHORE (European Photoreactor) outdoor simulation chamber facility in Valencia, Spain. EUPHORE is one of the largest and best-equipped facilities of its kind in the world, allowing investigation of atmospheric transformation processes under realistic ambient conditions (with dilutions in the range of 1:300). DE was generated on-site using a modern light-duty diesel engine and a dynamometer system equipped with a continuous emission-gas analyzer. The engine (a turbocharged, intercooled model with common-rail direct injection) was obtained from the Ford Motor Company. A first series of experiments was carried out in January 2005 (the winter 2005 campaign), a second in May 2005 (the summer 2005 campaign), and a third in May and June 2006 (the summer 2006 campaign). The diesel fuel that was used closely matched the one currently in use in most of the United States (containing 47 ppm sulfur and 15% aromatic compounds). Our experiments examined the effects on the composition of DE aged in the dark with added NO3 radicals and of DE aged in daylight with added OH radicals both with and without added volatile organic compounds (VOCs). In order to remove excess nitrogen oxides (NO(x)), a NO(x) denuder was devised and used to conduct experiments in realistic low-NO(x) conditions in both summer campaigns. A scanning mobility particle sizer was used to determine the particle size and the number and volume concentrations of particulate matter (PM) in the DE. O3, NO(x), and reactive nitrogen oxides (NO(y)) were monitored using chemiluminescence and Fourier transform infrared instruments. At the end of the exposures, samples of particle-associated and semivolatile organic compounds (SVOCs) were collected from the chamber for chemical analysis using an XAD-coated annular denuder followed by a filter and XAD cartridge. (XAD is an adsorbent polystyrene divinylbenzene resin used in sampling cartridges.) Samples for toxicity testing were collected using Teflon filters followed by two XAD cartridges. The chemical analyses included determination of organic carbon (OC), elemental carbon (EC), carbon fractions, inorganic ions (e.g., sulfate and nitrate), and speciated organic compounds (polycyclic aromatic hydrocarbons [PAHs], nitro-PAHs, polar compounds, alkanes, hopanes, and steranes). The toxicity tests were performed with extracts of PM combined with the SVOCs. The biologic activity of these extracts was evaluated in vivo by instilling them into the tracheas of rodents and measuring pulmonary toxicity, inflammation, and oxidative-stress responses. Results from the chemical analyses indicated that aging DE in the dark with added NO3 radicals and aging DE in daylight with and without additions led to the formation of additional particles and SVOC mass caused by reactions of VOCs, SVOCs, and inorganic gases. The greatest increase in mass occurred with the addition of VOCs as co-reactants. The proportions of the pyrolized OC (POC) fraction increased in the organic mass, which suggested that highly polar and oligomeric compounds had been formed. Results from the toxicity testing were consistent with the hypothesis that the toxicity of the samples had been affected by changes in their composition (caused both by the atmospheric aging and by changes in the initial composition of the DE presumably associated with changes in the engine, which was new at the outset and accrued wear during the study).
The role of T cells in the regulation of acrolein-induced pulmonary inflammation and epithelial-cell pathology.
Borchers MT, Wesselkamper SC, Deshmukh H … +5 more , Beckman E, Medvedovic M, Sartor M, Leikauf GD, HEI Health Review Committee
Res Rep Health Eff Inst · 2009 Dec · PMID 20218173
Exposure to acrolein in the ambient air in urban environments represents a considerable hazard to human health. Acrolein exposure causes airway inflammation, accumulation of monocytes, macrophages, and lymphocytes in the...
Exposure to acrolein in the ambient air in urban environments represents a considerable hazard to human health. Acrolein exposure causes airway inflammation, accumulation of monocytes, macrophages, and lymphocytes in the interstitium, mucous-cell metaplasia, and airspace enlargement. Currently, the mechanisms that control these events are unclear, and the relative contribution of T-cell subpopulations to pulmonary pathology after exposure to air toxics is unknown. In this study, we used a mouse model of pulmonary pathology induced by repeated acrolein exposure to examine whether pulmonary lymphocyte subpopulations differentially regulate inflammatory-cell accumulation and epithelial-cell pathology. To examine the role of the lymphocyte subpopulations, we used transgenic mice genetically deficient in either alphabeta T cells or gammadelta T cells and measured changes in several cellular, molecular, and pathologic outcomes associated with repeated inhalation exposure to 2.0 ppm or 0.5 ppm acrolein. To examine the potential functions of the lymphocyte subpopulations, we purified these cells from lung tissue of mice repeatedly exposed to 2.0 ppm acrolein, isolated and amplified the messenger RNA (mRNA*) transcripts, and performed oligonucleotide microarray analysis. Our data demonstrate that alphabeta T cells are primarily responsible for the accumulation of macrophages after acrolein exposure, whereas gammadelta T cells are the primary regulators of epithelial-cell homeostasis after repeated acrolein exposure. These findings are supported by the results of microarray analyses indicating that the two T-cell subpopulations have distinct gene-expression profiles after acrolein exposure. These data provide strong evidence that the T-cell subpopulations in the lung are major determinants of the response to pulmonary toxicant exposure and suggest that it is advantageous to elucidate the effector functions of these cells in the modulation of lung pathophysiology.
Effects of concentrated ambient particles and diesel engine exhaust on allergic airway disease in Brown Norway rats.
Harkema JR, Wagner JG, Kaminski NE … +5 more , Morishita M, Keeler GJ, McDonald JD, Barrett EG, HEI Health Review Committee
Res Rep Health Eff Inst · 2009 Nov · PMID 20198910
Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthm...
Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances epithelial remodeling of the airway and inflammation in rats previously sensitized to the allergen; and (2) exposure to DEE during OVA sensitization, or during OVA challenge, exacerbates epithelial remodeling of the airway and inflammation in rats. In the DEE studies, Brown Norway (BN) rats were sensitized with three daily intranasal (IN) instillations of 0.5% OVA, and then two weeks later were challenged with IN OVA or saline for 3 consecutive days. Rats were exposed to DEE diluted to mass concentrations of 30 or 300 microg/m3 diesel exhaust particles (DEPs) or to filtered air during either the sensitization or challenge periods. For the CAPs studies, the same OVA sensitization and challenge rat model was used but exposures to Detroit, Michigan, CAPs were limited to the OVA challenge period. Two separate 3-day CAPs exposures were conducted (week 1, high mean mass concentration = 595 microg/m3; week 2, low mean mass concentration = 356 microg/m3) during OVA challenge. In both the DEE and CAPs studies, rats were killed 24 hours after the last OVA challenge, bronchoalveolar lavage fluid (BALF) was collected and analyzed for cellularity and secreted mediators, and lungs and nose were processed for histopathologic examination and morphometric analysis of intraepithelial mucosubstances (IM). The results of our animal inhalation studies in the southwest (SW) Detroit community, an area with elevated ambient PM2.5 concentrations, suggested that, during allergen challenge, exposure to CAPs that were predominantly associated with emissions from combustion sources markedly enhanced the OVA-induced allergic airway disease, which was characterized by an increased infiltration in the lungs of eosinophilic and lymphocytic inflammation, increased IM in conducting airways, and increased concentrations in BALF of mucin-specific proteins and inflammatory cytokines. These findings suggest that urban airborne PM2.5 derived from stationary combustion sources (e.g., refineries, coal-burning power plants, waste-treatment plants) may enhance the development of human allergic airway diseases like childhood asthma. Previous animal inhalation studies in this community have also suggested that these fine, ambient combustion-derived particles may also exacerbate preexisting allergic airway disease. In contrast to our CAPs studies in Detroit, the controlled DEE exposures of allergen-sensitized BN rats, during either allergen sensitization or challenge periods, caused only a few mild modifications in the character of the allergen-induced disease. This finding contrasts with other reported studies that indicate that DEPs at relatively higher exposure doses do enhance allergic airway disease in some rodent models. The reasons for these disparities between studies likely reflect differences in exposure dose, animal models, the timing of exposures to the allergens and DEP exposures, the methods of allergen sensitization and challenge, or physicochemical differences among DEEs.
Air pollution and health: a European and North American approach (APHENA).
Katsouyanni K, Samet JM, Anderson HR … +13 more , Atkinson R, Le Tertre A, Medina S, Samoli E, Touloumi G, Burnett RT, Krewski D, Ramsay T, Dominici F, Peng RD, Schwartz J, Zanobetti A, HEI Health Review Committee
Res Rep Health Eff Inst · 2009 Oct · PMID 20073322
INTRODUCTION: This report provides the methodology and findings from the project: Air Pollution and Health: a European and North American Approach (APHENA). The principal purpose of the project was to provide an understa...
INTRODUCTION: This report provides the methodology and findings from the project: Air Pollution and Health: a European and North American Approach (APHENA). The principal purpose of the project was to provide an understanding of the degree of consistency among findings of multicity time-series studies on the effects of air pollution on mortality and hospitalization in several North American and European cities. The project included parallel and combined analyses of existing data. The investigators sought to understand how methodological differences might contribute to variation in effect estimates from different studies, to characterize the extent of heterogeneity in effect estimates, and to evaluate determinants of heterogeneity. The APHENA project was based on data collected by three groups of investigators for three earlier studies: (1) Air Pollution and Health: A European Approach (APHEA), which comprised two multicity projects in Europe. (Phase 1 [APHEA1] involving 15 cities, and Phase 2 [APHEA2] involving 32 cities); (2) the National Morbidity, Mortality, and Air Pollution Study (NMMAPS), conducted in the 90 largest U.S. cities; and (3) multicity research on the health effects of air pollution in 12 Canadian cities. METHODS: The project involved the initial development of analytic approaches for first-stage and second-stage analyses of the time-series data and the subsequent application of the resulting methods to the time-series data. With regard to the first-stage analysis, the various investigative groups had used conceptually similar approaches to the key issues of controlling for temporal confounding and temperature; however, specific methods differed. Consequently, the investigators needed to establish a standard protocol, but one that would be linked to prior approaches. Based on exploratory analyses and simulation studies, a first-stage analysis protocol was developed that used generalized linear models (GLM) with either penalized splines (PS) or natural splines (NS) to adjust for seasonality, with 3, 8, or 12 degrees of freedom (df) per year and also the number of degrees of freedom chosen by minimizing the partial autocorrelation function (PACF) of the model's residuals. For hospitalization data, the approach for model specification followed that used for mortality, accounting for seasonal patterns, but also, for weekend and vacation effects, and for epidemics of respiratory disease. The data were also analyzed to detect potential thresholds in the concentration-response relationships. The second-stage analysis used pooling approaches and assessed potential effect modification by sociodemographic characteristics and indicators of the pollution mixture across study regions. Specific quality control exercises were also undertaken. Risks were estimated for two pollutants: particulate matter - 10 pm in aerodynamic diameter (PM10) and ozone (O3). RESULTS: The first-stage analysis yielded estimates that were relatively robust to the underlying smoothing approach and to the number of degrees of freedom. The first-stage APHENA results generally replicated the previous independent analyses performed by the three groups of investigators. PM10 effects on mortality risk estimates from the APHEA2 and NMMAPS databases were quite close, while estimates from the Canadian studies were substantially higher. For hospitalization, results were more variable without discernable patterns of variation among the three data sets. PM10 effect-modification patterns, explored only for cities with daily pollution data (i.e., 22 in Europe and 15 in the U.S.), were not entirely consistent across centers. Thus, the levels of pollutants modified the effects differently in Europe than in the United States. Climatic variables were important only in Europe. In both Europe and the United States, a higher proportion of older persons in the study population was associated with increased PM10 risk estimates, as was a higher rate of unemployment - the sole indicator of socioeconomic status uniformly available across the data sets. APHENA study results on the effects of O3 on mortality were less comprehensive than for PM10 because the studies from the three regions varied in whether they analyzed data for the full year or only for the summer months. The effects tended to be larger for summer in Europe and the United States. In the United States they were lower when controlled for PM10. The estimated effect of O3 varied by degrees of freedom and across the three geographic regions. The effects of O3 on mortality were larger in Canada, and there was little consistent indication of effect modification in any location. CONCLUSIONS: APHENA has shown that mortality findings obtained with the new standardized analysis were generally comparable to those obtained in the earlier studies, and that they were relatively robust to the data analysis method used. For PM10, the effect-modification patterns observed were not entirely consistent between Europe and the United States. For O3, there was no indication of strong effect modification in any of the three data sets.
Genotoxicity of 1,3-butadiene and its epoxy intermediates.
Walker VE, Walker DM, Meng Q … +9 more , McDonald JD, Scott BR, Seilkop SK, Claffey DJ, Upton PB, Powley MW, Swenberg JA, Henderson RF, Health Review Committee
Res Rep Health Eff Inst · 2009 Aug · PMID 20017413
Current risk assessments of 1,3-butadiene (BD*) are complicated by limited evidence of its carcinogenicity in humans. Hence, there is a critical need to identify early events and factors that account for the heightened s...
Current risk assessments of 1,3-butadiene (BD*) are complicated by limited evidence of its carcinogenicity in humans. Hence, there is a critical need to identify early events and factors that account for the heightened sensitivity of mice to BD-induced carcinogenesis and to deter-mine which animal model, mouse or rat, is the more useful surrogate of potency for predicting health effects in BD-exposed humans. HEI sponsored an earlier investigation of mutagenic responses in mice and rats exposed to BD, or to the racemic mixture of 1,2-epoxy-3-butene (BDO) or of 1,2,3,4-diepoxybutane (BDO2; Walker and Meng 2000). In that study, our research team demonstrated (1) that the frequency of mutations in the hypoxanthine-guanine phosphoribosyl transferase (Hprt) gene of splenic T cells from BD-exposed mice and rats could be correlated with the species-related differences in cancer susceptibility; (2) that mutagenic-potency and mutagenic-specificity data from mice and rats exposed to BD or its individual epoxy intermediates could provide useful information about the BD metabolites responsible for mutations in each species; and (3) that our novel approach to measuring the mutagenic potency of a given chemical exposure as the change in Hprt mutant frequencies (Mfs) over time was valuable for estimating species-specific differences in mutagenic responses to BD exposure and for predicting the effect of BD metabolites in each species. To gain additional mode-of-action information that can be used to inform studies of human responses to BD exposure, experiments in the current investigation tested a new set of five hypotheses about species-specific patterns in the mutagenic effects in rodents of exposure to BD and BD metabolites: 1. Repeated BD exposures at low levels that approach the occupational exposure limit for BD workers (set by the U.S. Occupational Safety and Health Administration) are mutagenic in female mice. 2. The differences in mutagenic responses of the Hprt gene to BD in similarly exposed rodents of a given species (reported in various earlier studies) are primarily associated with age-related thymus activity and trafficking of T cells and with sex-related differences in BD metabolism. 3. The mutagenic potency of the stereochemical forms of BD's epoxy intermediates plays a significant role in the species-related mutagenicity of BD. 4. The hydrolysis-detoxification pathway of BD through 1,2-dihydroxy-3-butene (BD-diol) is a major contributor to mutagenicity at high-level BD exposures in mice and rats. 5. Significant and informative species-specific differences in mutation spectra can be identified by examining both large- and small-scale genetic alterations in the Hprt gene of BD-exposed mice and rats. The first four hypotheses were tested by exposing mice and rats to BD, meso-BDO2, or BD-diol and measuring Hprt Mfs as the primary biomarker. For this, we used the T-cell-cloning assay of lymphocytes isolated from the spleens of exposed and control (sham-exposed) mice and rats. The first hypothesis was tested by exposing female B6C3F1 mice (4 to 5 weeks of age) by inhalation for 2 weeks (6 hours/day, 5 days/week) to 0 or 3 ppm BD. Hprt Mfs were measured at the time of peak mutagenic response after exposure for this age of mice. We then compared the resulting data to those from mutagenicity studies with mice of the same age that had been exposed in a similar protocol to higher levels of BD (Walker and Meng 2000). In mice exposed to 3 ppm BD (n = 27), there was a significant 1.6-fold increase over the mean background Hprt Mf in control animals (n = 24, P = 0.004). Calculating the efficiency of Hprt mutant induction, by dividing induced Hprt Mfs by the respective BD exposure levels, demonstrated that the mutagenic potency of 3 ppm BD was twice that of 20 ppm BD and almost 20 times that of 625 or 1250 ppm BD in exposed female mice. Sample-size calculations based on the Hprt Mf data from this experiment demonstrated the feasibility of conducting a future experiment to find out whether induced Mfs at even lower exposure levels (between 0.1 and 1.0 ppm BD) fit the supralinear exposure-response curve found with exposures between 3.0 and 62.5 ppm BD, or whether they deviate from the curve as Mf values approach the background levels found in control animals. The second hypothesis was tested by estimating mutagenic potency for female mice exposed by inhalation for 2 weeks to 0 or 1250 ppm BD at 8 weeks of age and comparing this estimate to that reported for female mice exposed to BD in a similar protocol at 4 to 5 weeks of age (Walker and Meng 2000). For these two age groups, the shapes of the mutant splenic T-cell manifestation curves were different, but the mutagenic burden was statistically the same. These results support our contention that the disparity in responses reported in earlier Hprt-mutation studies of BD-exposed rodents is related more to age-related T-cell kinetics than to age-specific differences in the metabolism of BD. The third hypothesis was tested by estimating mutagenic potency for female mice and rats (4 to 5 weeks of age) exposed by inhalation to 2 or 4 ppm meso-BDO2 and comparing these estimates to those previously obtained for female mice and rats of the same age and exposed in a similar protocol to (+/-)-BDO2 (Meng et al. 1999b; Walker and Meng 2000). These exposures to stereospecific forms of BDO2 caused equivalent mutagenic effects in each species. This suggests that the small differences in the mutagenic potency of the individual stereoisomers of BDO2 appear to be of less consequence in characterizing the sources of BD-induced mutagenicity than the much larger differences between the mutagenic potencies of BDO2 and the other two BD epoxides (BDO and 1,2-dihydroxy-3,4-epoxybutane [BDO-diol]). The fourth hypothesis was tested in several experiments. First, female and male mice and rats (4 to 5 weeks of age) were exposed by nose only for 6 hours to 0, 62.5, 200, 625, or 1250 ppm BD or to 0, 6, 18, 24, or 36 ppm BD-diol primarily to establish BD and BD-diol exposure levels that would yield similar plasma concentrations of BD-diol. Second, animals were exposed in inhalation chambers for 4 weeks to 0, 6, 18, or 36 ppm BD-diol to determine the mutagenic potency estimates for these exposure levels and to compare these estimates with those reported for BD-exposed female mice and rats (Walker and Meng 2000) in which similar blood levels of BD-diol had been achieved. Measurements of plasma concentrations of BD-diol (via a gas chromatography and mass spectrometry [GC/MS] method developed for this purpose) showed these results: First, BD-diol accumulated in a sublinear manner during a single 6-hour exposure to more than 200 ppm BD. Second, BD-diol accumulated in a linear manner during single (6-hour) or repeated (4-week) exposure to 6 or 18 ppm BD and in a sublinear manner with increasing levels of BD-diol exposure. Third, exposure of female mice and rats to 18 ppm BD-diol produced plasma concentrations equivalent to those produced by exposure to 200 ppm BD (exposure to 36 ppm BD-diol produced plasma concentrations of about 25% of those produced by exposure to 625 ppm BD). In general, 4-week exposure to 18 or 36 ppm BD-diol was significantly mutagenic in female and male mice and rats. The differences in mutagenic responses between the species and sexes were not remarkable, except that the mutagenic effects were greatest in female mice. The substantial differences in the exposure-related accumulation of BD-diol in plasma after rodents were exposed to more than 200 ppm BD compared with the relatively small differences in the mutagenic responses to direct exposures to 6, 18, or 36 ppm BD-diol in female mice provided evidence that the contribution of BD-diol-derived metabolites to the overall mutagenicity of BD has a narrow range of effect that is confined to relatively high-level BD exposures in mice and rats. This conclusion was supported by the results of parallel analyses of adducts in mice and rats concurrently exposed to BD-diol (Powley et al. 2005b), which showed that the exposure-response curves for the formation of N-(2,3,4-trihydroxybutyl)valine (THB-Val) in hemoglobin, formation of N7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) in DNA, and induction of Hprt mutations in exposed rodents were remarkably similar in shape (i.e., supralinear). Combined, these data suggest that trihydroxybutyl (THB) adducts are good quantitative indicators of BD-induced mutagenicity and that BD-diol-derived BDO-diol (the major source of the adducts) might be largely responsible for mutagenicity in rodents exposed to BD-diol or to hight levels of BD. The mutagenic-potency studies of meso-BDO2 and BD-diol reported here, combined with our earlier studies of BD, (+/-) BDO, and(+/-)-BDO2 (Walker and Meng 2000), revealed important trends in species-specific mutagenic responses that distinguish the relative degree to which the epoxy intermediates contribute to mutation induction in rodents at selected levels of BD exposures. These data as a whole suggest that , in mice, BDO2 largely causes mutations at exposures less than 62.5 ppm BD and that BD-diol-derived metabolites add to these mutagenic effects at higher BD exposures. In rats, it appears that the BD-diol pathway might account for nearly all the mutagenicity at the hight-level BD exposures where significant increases in Hprt Mfs are found and cancers are induced. Additional exposure-response studies of hemoglobin and DNA adducts specifics to BDO2, BDO-diol, and other reactive intermediates are needed to determine more definitively the relative contribution of each metabolite to the DNA alkylation and mutation patterns induced by BD exposure in mice and rats. For the fifth hypothesis, a multiplex polymerase chain reaction (PCR) procedure for the analysis of genomic DNA mutations in the Hprt gene of mice was developed. (ABSTRACT TRUNCATED)
Measurement and modeling of exposure to selected air toxics for health effects studies and verification by biomarkers.
Harrison RM, Delgado-Saborit JM, Baker SJ … +7 more , Aquilina N, Meddings C, Harrad S, Matthews I, Vardoulakis S, Anderson HR, HEI Health Review Committee
Res Rep Health Eff Inst · 2009 Jun · PMID 19999825
The overall aim of our investigation was to quantify the magnitude and range of individual personal exposures to a variety of air toxics and to develop models for exposure prediction on the basis of time-activity diaries...
The overall aim of our investigation was to quantify the magnitude and range of individual personal exposures to a variety of air toxics and to develop models for exposure prediction on the basis of time-activity diaries. The specific research goals were (1) to use personal monitoring of non-smokers at a range of residential locations and exposures to non-traffic sources to assess daily exposures to a range of air toxics, especially volatile organic compounds (VOCs) including 1,3-butadiene and particulate polycyclic aromatic hydrocarbons (PAHs); (2) to determine microenvironmental concentrations of the same air toxics, taking account of spatial and temporal variations and hot spots; (3) to optimize a model of personal exposure using microenvironmental concentration data and time-activity diaries and to compare modeled exposures with exposures independently estimated from personal monitoring data; (4) to determine the relationships of urinary biomarkers with the environmental exposures to the corresponding air toxic. Personal exposure measurements were made using an actively pumped personal sampler enclosed in a briefcase. Five 24-hour integrated personal samples were collected from 100 volunteers with a range of exposure patterns for analysis of VOCs and 1,3-butadiene concentrations of ambient air. One 24-hour integrated PAH personal exposure sample was collected by each subject concurrently with 24 hours of the personal sampling for VOCs. During the period when personal exposures were being measured, workplace and home concentrations of the same air toxics were being measured simultaneously, as were seasonal levels in other microenvironments that the subjects visit during their daily activities, including street microenvironments, transport microenvironments, indoor environments, and other home environments. Information about subjects' lifestyles and daily activities were recorded by means of questionnaires and activity diaries. VOCs were collected in tubes packed with the adsorbent resins Tenax GR and Carbotrap, and separate tubes for the collection of 1,3-butadiene were packed with Carbopack B and Carbosieve S-III. After sampling, the tubes were analyzed by means of a thermal desorber interfaced with a gas chromatograph-mass spectrometer (GC-MS). Particle-phase PAHs collected onto a quartz-fiber filter were extracted with solvent, purified, and concentrated before being analyzed with a GC-MS. Urinary biomarkers were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Both the environmental concentrations and personal exposure concentrations measured in this study are lower than those in the majority of earlier published work, which is consistent with the reported application of abatement measures to the control of air toxics emissions. The environmental concentration data clearly demonstrate the influence of traffic sources and meteorologic conditions leading to higher air toxics concentrations in the winter and during peak-traffic hours. The seasonal effect was also observed in indoor environments, where indoor sources add to the effects of the previously identified outdoor sources. The variability of personal exposure concentrations of VOCs and PAHs mainly reflects the range of activities the subjects engaged in during the five-day period of sampling. A number of generic factors have been identified to influence personal exposure concentrations to VOCs, such as the presence of an integral garage (attached to the home), exposure to environmental tobacco smoke (ETS), use of solvents, and commuting. In the case of the medium- and high-molecular-weight PAHs, traffic and ETS are important contributions to personal exposure. Personal exposure concentrations generally exceed home indoor concentrations, which in turn exceed outdoor concentrations. The home microenvironment is the dominant individual contributor to personal exposure. However, for those subjects with particularly high personal exposures, activities within the home and exposure to ETS play a major role in determining exposure. Correlation analysis and principal components analysis (PCA) have been performed to identify groups of compounds that share common sources, common chemistry, or common transport or meteorologic patterns. We used these methods to identify four main factors determining the makeup of personal exposures: fossil fuel combustion, use of solvents, ETS exposure, and use of consumer products. Concurrent with sampling of the selected air toxics, a total of 500 urine samples were collected, one for each of the 100 subjects on the day after each of the five days on which the briefcases were carried for personal exposure data collection. From the 500 samples, 100 were selected to be analyzed for PAHs and ETS-related urinary biomarkers. Results showed that urinary biomarkers of ETS exposure correlated strongly with the gas-phase markers of ETS and 1,3-butadiene. The urinary ETS biomarkers also correlated strongly with high-molecular-weight PAHs in the personal exposure samples. Five different approaches have been taken to model personal exposure to VOCs and PAHs, using 75% of the measured personal exposure data set to develop the models and 25% as an independent check on the model performance. The best personal exposure model, based on measured microenvironmental concentrations and lifestyle factors, is able to account for about 50% of the variance in measured personal exposure to benzene and a higher proportion of the variance for some other compounds (e.g., 75% of the variance in 3-ethenylpyridine exposure). In the case of the PAHs, the best model for benzo[a]pyrene is able to account for about 35% of the variance among exposures, with a similar result for the rest of the PAH compounds. The models developed were validated by the independent data set for almost all the VOC compounds. The models developed for PAHs explain some of the variance in the independent data set and are good indicators of the sources affecting PAH concentrations but could not be validated statistically, with the exception of the model for pyrene. A proposal for categorizing personal exposures as low or high is also presented, according to exposure thresholds. For both VOCs and PAHs, low exposures are correctly classified for the concentrations predicted by the proposed models, but higher exposures were less successfully classified.
Extended follow-up and spatial analysis of the American Cancer Society study linking particulate air pollution and mortality.
Krewski D, Jerrett M, Burnett RT … +18 more , Ma R, Hughes E, Shi Y, Turner MC, Pope CA, Thurston G, Calle EE, Thun MJ, Beckerman B, DeLuca P, Finkelstein N, Ito K, Moore DK, Newbold KB, Ramsay T, Ross Z, Shin H, Tempalski B
Res Rep Health Eff Inst · 2009 May · PMID 19627030
We conducted an extended follow-up and spatial analysis of the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) cohort in order to further examine associations between long-term exposure to particulate a...
We conducted an extended follow-up and spatial analysis of the American Cancer Society (ACS) Cancer Prevention Study II (CPS-II) cohort in order to further examine associations between long-term exposure to particulate air pollution and mortality in large U.S. cities. The current study sought to clarify outstanding scientific issues that arose from our earlier HEI-sponsored Reanalysis of the original ACS study data (the Particle Epidemiology Reanalysis Project). Specifically, we examined (1) how ecologic covariates at the community and neighborhood levels might confound and modify the air pollution-mortality association; (2) how spatial autocorrelation and multiple levels of data (e.g., individual and neighborhood) can be taken into account within the random effects Cox model; (3) how using land-use regression to refine measurements of air pollution exposure to the within-city (or intra-urban) scale might affect the size and significance of health effects in the Los Angeles and New York City regions; and (4) what exposure time windows may be most critical to the air pollution-mortality association. The 18 years of follow-up (extended from 7 years in the original study [Pope et al. 1995]) included vital status data for the CPS-II cohort (approximately 1.2 million participants) with multiple cause-of-death codes through December 31, 2000 and more recent exposure data from air pollution monitoring sites for the metropolitan areas. In the Nationwide Analysis, the influence of ecologic covariate data (such as education attainment, housing characteristics, and level of income; data obtained from the 1980 U.S. Census; see Ecologic Covariates sidebar on page 14) on the air pollution-mortality association were examined at the Zip Code area (ZCA) scale, the metropolitan statistical area (MSA) scale, and by the difference between each ZCA value and the MSA value (DIFF). In contrast to previous analyses that did not directly include ecologic covariates at the ZCA scale, risk estimates increased when ecologic covariates were included at all scales. The ecologic covariates exerted their greatest effect on mortality from ischemic heart disease (IHD), which was also the health outcome most strongly related with exposure to PM2.5 (particles 2.5 microm or smaller in aerodynamic diameter), sulfate (SO4(2-)), and sulfur dioxide (SO2), and the only outcome significantly associated with exposure to nitrogen dioxide (NO2). When ecologic covariates were simultaneously included at both the MSA and DIFF levels, the hazard ratio (HR) for mortality from IHD associated with PM2.5 exposure (average concentration for 1999-2000) increased by 7.5% and that associated with SO4(2-) exposure (average concentration for 1990) increased by 12.8%. The two covariates found to exert the greatest confounding influence on the PM2.5-mortality association were the percentage of the population with a grade 12 education and the median household income. Also in the Nationwide Analysis, complex spatial patterns in the CPS-II data were explored with an extended random effects Cox model (see Glossary of Statistical Terms at end of report) that is capable of clustering up to two geographic levels of data. Using this model tended to increase the HR estimate for exposure to air pollution and also to inflate the uncertainty in the estimates. Including ecologic covariates decreased the variance of the results at both the MSA and ZCA scales; the largest decrease was in residual variation based on models in which the MSA and DIFF levels of data were included together, which suggests that partitioning the ecologic covariates into between-MSA and within-MSA values more completely captures the sources of variation in the relationship between air pollution, ecologic covariates, and mortality. Intra-Urban Analyses were conducted for the New York City and Los Angeles regions. The results of the Los Angeles spatial analysis, where we found high exposure contrasts within the Los Angeles region, showed that air pollution-mortality risks were nearly 3 times greater than those reported from earlier analyses. This suggests that chronic health effects associated with intra-urban gradients in exposure to PM2.5 may be even larger between ZCAs within an MSA than the associations between MSAs that have been previously reported. However, in the New York City spatial analysis, where we found very little exposure contrast between ZCAs within the New York region, mortality from all causes, cardiopulmonary disease (CPD), and lung cancer was not elevated. A positive association was seen for PM2.5 exposure and IHD, which provides evidence of a specific association with a cause of death that has high biologic plausibility. These results were robust when analyses controlled (1) the 44 individual-level covariates (from the ACS enrollment questionnaire in 1982; see 44 Individual-Level Covariates sidebar on page 22) and (2) spatial clustering using the random effects Cox model. Effects were mildly lower when unemployment at the ZCA scale was included. To examine whether there is a critical exposure time window that is primarily responsible for the increased mortality associated with ambient air pollution, we constructed individual time-dependent exposure profiles for particulate and gaseous air pollutants (PM2.5 and SO2) for a subset of the ACS CPS-II participants for whom residence histories were available. The relevance of the three exposure time windows we considered was gauged using the magnitude of the relative risk (HR) of mortality as well as the Akaike information criterion (AIC), which measures the goodness of fit of the model to the data. For PM2.5, no one exposure time window stood out as demonstrating the greatest HR; nor was there any clear pattern of a trend in HR going from recent to more distant windows or vice versa. Differences in AIC values among the three exposure time windows were also small. The HRs for mortality associated with exposure to SO2 were highest in the most recent time window (1 to 5 years), although none of these HRs were significantly elevated. Identifying critical exposure time windows remains a challenge that warrants further work with other relevant data sets. This study provides additional support toward developing cost-effective air quality management policies and strategies. The epidemiologic results reported here are consistent with those from other population-based studies, which collectively have strongly supported the hypothesis that long-term exposure to PM2.5 increases mortality in the general population. Future research using the extended Cox-Poisson random effects methods, advanced geostatistical modeling techniques, and newer exposure assessment techniques will provide additional insight.
Air pollution effects on ventricular repolarization.
Lux RL, Pope CA
Res Rep Health Eff Inst · 2009 May · PMID 19579527
We conducted a retrospective study of a set of previously published electrocardiographic data to investigate the possible direct association between levels of particulate air pollution and changes in ventricular repolari...
We conducted a retrospective study of a set of previously published electrocardiographic data to investigate the possible direct association between levels of particulate air pollution and changes in ventricular repolarization -- the cardiac electrophysiologic process that manifests itself as the T wave* of the electrocardiogram (ECG) and that is definitively linked to and responsible for increased arrhythmogenesis. The published findings from this data set demonstrated a clear cardiac effect, namely, a reduction in heart rate variability (HRV) parameter values with increased levels of particulate air pollution (Pope et al. 2004), suggesting possible arrhythmogenic effects. Given this positive finding and the well-established sensitivity of cardiac repolarization to physiologic, pharmacologic, and neurologic interventions, and in light of emerging novel tools for assessing repolarization, we hypothesized that high levels of particulate air pollution would alter repolarization independent of changes in heart rate and, consequently, would increase arrhythmogenic risk. The likely mechanism of any deleterious effects on repolarization would be alteration of sodium, calcium, and potassium channels. The channel's structure, function, and kinetics are responsible for generating the cellular action potentials, which, when summed over the entire heart, result in the waves recorded by the ECG. A positive finding would provide evidence that increased levels of air pollution may be directly linked to increases in arrhythmogenic risk and, potentially, sudden cardiac death. The study population consisted of 88 nonsmoking, elderly subjects in whom multiple, continuous, 24-hour, 2-channel ECG recordings were collected, along with blood samples to evaluate inflammatory mechanisms (not pursued in the current study). The concentration of fine particulate matter (PM2.5, particulate matter with an aerodynamic diameter < or = 2.5 microm) in daily samples was measured or estimated and used to trigger recording sessions for days considered to have "low" or "high" PM2.5 concentrations. Each subject participated in one to five recordings over the study period, and all subjects lived within the greater Salt Lake Valley in Utah. We reanalyzed these recordings using custom software that incorporated a magnitude function of the ECG -- the root mean square of all recorded leads (RMS ECG) -- to determine the following for each beat in the 24-hour recording: cycle length (RR); RR dispersion; the interval between the RMS R- and T-wave peaks (RT), a robust estimate of mean duration of ventricular action potential; the width of the RMS T wave (TW), a robust estimate of the range of repolarization times that relates to repolarization dispersion and arrhythmogenesis; the RMS QT interval (QT) measured from the QRS onset to T-wave offset of the RMS ECG; and the regression slopes of RT versus RR, QT versus RR, and TW versus RR, which provide estimates of so-called repolarization restitution, or rate dependency of repolarization, which also is associated with arrhythmogenesis. The study findings did not support the original hypothesis and demonstrated a lack of sensitivity of repolarization to changes in PM2.5 concentrations. None of the repolarization variables showed a statistically significant change between days of low and high PM2.5 concentrations, although we observed statistically significant differences for some variables using fixed-effects modeling. However, we did find a significant decrease in the standard deviation of cycle length, in concert with findings in the original study that showed a decrease in HRV parameter values. There was a slight but statistically insignificant increase in the width of the TW between recordings from days of low and days of high PM2.5, suggesting that, in a setting of prolonged exposure to high levels of PM, the original hypothesis might be supported. We conclude that in this study the short-term (day-today) differences in air pollution, specifically PM2.5 concentration, did not affect ventricular repolarization. A likely explanation for the negative result is that the day-today variability of repolarization (arising from autonomic influences, activity, and heart rate) far outweighs the changes that might be induced by air pollution, if any. In addition, the study may have been underpowered. The findings do not refute the possibility of the deleterious repolarization effects of PM, particularly over prolonged periods of exposure, but suggest the need for exposure studies that provide better controls. In light of recent studies, it is also likely that in an at-risk population -- for example, patients compromised with heart disease -- repolarization changes may be more apparent.
Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR study.
Brunekreef B, Beelen R, Hoek G … +7 more , Schouten L, Bausch-Goldbohm S, Fischer P, Armstrong B, Hughes E, Jerrett M, van den Brandt P
Res Rep Health Eff Inst · 2009 Mar · PMID 19554969
Evidence is increasing that long-term exposure to ambient air pollution is associated with deaths from cardiopulmonary diseases. In a 2002 pilot study, we reported clear indications that traffic-related air pollution, es...
Evidence is increasing that long-term exposure to ambient air pollution is associated with deaths from cardiopulmonary diseases. In a 2002 pilot study, we reported clear indications that traffic-related air pollution, especially at the local scale, was related to cardiopulmonary mortality in a randomly selected subcohort of 5000 older adults participating in the ongoing Netherlands Cohort Study (NLCS) on diet and cancer. In the current study, referred to as NLCS-AIR, our objective was to obtain more precise estimates of the effects of traffic-related air pollution by analyzing associations with cause-specific mortality, as well as lung cancer incidence, in the full cohort of approximately 120,000 subjects. Cohort members were 55 to 69 years of age at enrollment in 1986. Follow-up was from 1987 through 1996 for mortality (17,674 deaths) and from late 1986 through 1997 for lung cancer incidence (2234 cases). Information about potential confounding variables and effect modifiers was available from the questionnaire that subjects completed at enrollment and from publicly available data (including neighborhood-scale information such as income distributions). The NLCS was designed for a case-cohort approach, which makes use of all the cases in the full cohort, while data for the random subcohort are used to estimate person-time experience in the study. Full information on confounders was available for the subjects in the random subcohort and for the emerging cases of mortality and lung cancer incidence during the follow-up period, and in NLCS-AIR we used the case-cohort approach to examine the relation between exposure to air pollution and cause-specific mortality and lung cancer. We also specified a standard Cox proportional hazards model within the full cohort, for which information on potential confounding variables was much more limited. Exposure to air pollution was estimated for the subjects' home addresses at baseline in 1986. Concentrations were estimated for black smoke (a simple marker for soot) and nitrogen dioxide (NO2) as indicators of traffic-related air pollution, as well as nitric oxide (NO), sulfur dioxide (SO2), and particulate matter with aerodynamic diameter < or = 2.5 microm (PM2.5), as estimated from measurements of particulate matter with aerodynamic diameter < or = 10 microm (PM10). Overall long-term exposure concentrations were considered to be a function of air pollution contributions at regional, urban, and local scales. We used interpolation from data obtained routinely at regional stations of the National Air Quality Monitoring Network (NAQMN) to estimate the regional component of exposure at the home address. Average pollutant concentrations were estimated from NAQMN measurements for the period 1976 through 1996. Land-use regression methods were used to estimate the urban exposure component. For the local exposure component, geographic information systems (GISs) were used to generate indicators of traffic exposure that included traffic intensity on and distance to nearby roads. A major effort was made to collect traffic intensity data from individual municipalities. The exposure variables were refined considerably from those used in the pilot study, but we also analyzed the data for the full cohort in the current study using the exposure indicators of the pilot study. We analyzed the data in models with the estimated overall pollutant concentration as a single variable and with the background concentration (the sum of regional and urban components) and the local exposure estimate from traffic indicators as separate variables. In the full-cohort analyses adjusted for the limited set of confounders, estimated overall exposure concentrations of black smoke, NO2, NO, and PM2.5 were associated with mortality. For a 10-microg/m3 increase in the black smoke concentration, the relative risk (RR) (95% confidence interval [CI]) was 1.05 (1.00-1.11) for natural-cause (nonaccidental) mortality, 1.04 (0.95-1.13) for cardiovascular mortality, 1.22 (0.99-1.50) for respiratory mortality, 1.03 (0.88-1.20) for lung cancer mortality, and 1.04 (0.97-1.12) for noncardiopulmonary, non-lung cancer mortality. Results were similar for NO2, NO, and PM2.5. For a 10-microg/m3 increase in PM2.5 concentration, the RR for natural-cause mortality was 1.06 (95% CI, 0.97-1.16), the same as in the results of the American Cancer Society Study reported by Pope and colleagues in 2002. The highest relative risks were found for respiratory mortality, though confidence intervals were wider for this less-frequent cause of death. No associations with mortality were found for SO2. Some of the associations between the traffic indicator variables used to assess traffic intensity near the home and mortality reached statistical significance in the full cohort. For an increase in traffic intensity of 10,000 motor vehicles in 24 hours (motor vehicles/day) on the road nearest a subject's residence, the RR was 1.03 (95% CI, 1.00-1.08) for natural-cause mortality, 1.05 (0.99-1.12) for cardiovascular mortality, 1.10 (0.95-1.26) for respiratory mortality, 1.07 (0.96-1.19) for lung cancer mortality, and 1.00 (0.94-1.06) for noncardiopulmonary, non-lung cancer mortality. Results were similar for traffic intensity in a 100-m buffer around the subject's residence and living near a major road (a road with more than 10,000 motor vehicles/day). Distance in meters to the nearest major road and traffic intensity on the nearest major road were not associated with any of the mortality outcomes. We did not find an association between cardiopulmonary mortality and living near a major road as defined using the methods of the pilot study. In the case-cohort analyses adjusted for all potential confounders, we found no associations between background air pollution and mortality. The associations between traffic intensity and mortality were weaker than in the full cohort, and confidence intervals were wider, consistent with the smaller number of subjects. The lower relative risks of mortality associated with traffic variables in the case-cohort study population could be related to the particular subcohort that was randomly selected from the full cohort, as the risks estimated with the actual subcohort were well below the average estimates obtained for 100 new case-cohort analyses with 100 alternative subcohorts of 5000 subjects each that we randomly selected from the full cohort. Differences in adjusted relative risks between the full-cohort and the case-cohort analyses could be explained by random error introduced by sampling from the full cohort and by a selection effect resulting from the relatively large number of missing data for variables in the extensive confounder model used in the case-cohort analyses. More complete control for confounding probably did not contribute much to the lower relative risks in the case-cohort analyses, especially for the traffic variables, as results were similar when the limited confounder model for the full cohort was used in analyses of the subjects in the case-cohort study population. In additional analyses using black smoke concentrations as the exposure variables, we found that the association between overall black smoke and cardiopulmonary mortality was somewhat stronger for case-cohort subjects who did not change residence during follow-up, and in the full cohort, there was a tendency for relative risks to be higher for subjects living in the three major cities included in the study. Adjustment for estimated exposure to traffic noise did not affect the associations of background black smoke and traffic intensity with cardiovascular mortality. There was some indication of an association between traffic noise and cardiovascular mortality only for the 1.6% of the subjects in the full cohort who were exposed to traffic noise in the highest category of > 65 A-weighted decibels (dB(A); decibels with the sound pressure scale adjusted to conform with the frequency response of the human ear). Examination of sex, smoking status, educational level, and vegetable and fruit intake as possible effect modifiers showed that for overall black smoke concentrations, associations with mortality tended to be stronger in case-cohort subjects with lower levels of education and those with low fruit intake, but differences between strata were not statistically significant. For lung cancer incidence, we found essentially no relation to exposure to NO2, black smoke, PM2.5, SO2, or several traffic indicators. Associations of overall air pollution concentrations and traffic indicator variables with lung cancer incidence were, however, found in subjects who had never smoked, with an RR of 1.47 (95% CI, 1.01-2.16) for a 10-microg/m3 increase in overall black smoke concentration. In the current study, the mortality risks associated with both background air pollution and traffic exposure variables were much smaller than the estimate previously reported in the pilot study for risk of cardiopulmonary mortality associated with living near a major road (RR, 1.95; 95% CI, 1.09-3.51). The differences are most likely due to the extension of the follow-up period in the current study and to random error in the pilot study related to sampling from the full cohort. Though relative risks were generally small in the current study, long-term average concentrations of black smoke, NO2, and PM2.5 were related to mortality, and associations of black smoke and NO2 exposure with natural-cause and respiratory mortality were statistically significant. Traffic intensity near the home was also related to natural-cause mortality. The highest relative risks associated with background air pollution and traffic variables were for respiratory mortality, though the number of deaths was smaller than for the other mortality categories. (ABSTRACT TRUNCATED)
The influence of improved air quality on mortality risks in Erfurt, Germany.
Peters A, Breitner S, Cyrys J … +7 more , Stölzel M, Pitz M, Wölke G, Heinrich J, Kreyling W, Küchenhoff H, Wichmann HE
Res Rep Health Eff Inst · 2009 Feb · PMID 19554968
Around the world, daily variations in ambient air pollution have been consistently associated with variations in daily mortality. The aim of the study presented here was to assess the effects of ambient air pollution on...
Around the world, daily variations in ambient air pollution have been consistently associated with variations in daily mortality. The aim of the study presented here was to assess the effects of ambient air pollution on daily mortality during a period of tremendous changes in air quality in the city of Erfurt, in eastern Germany, from October 1991 to March 2002. Data on particle size distributions were obtained from September 1995 to March 2002 at a research monitoring station. For particles from 0.01 microm to 2.5 microm in diameter, number concentrations (NCs)* and mass concentrations (MCs) were calculated. Particles with diameters less than or equal to 0.10 microm are defined as ultrafine particles (UFP). Data on the gaseous pollutants NO2, CO, SO2, and O3 and on PM10 (particulate matter [PM] with aerodynamic diameter less than or equal to 10 microm) were obtained from a government air-monitoring station. Data on changes in energy consumption, car fleet composition, and population were collected from local authorities. Death certificates of persons living in and dying in Erfurt were abstracted, and daily mortality counts were calculated. Poisson regression models were used to analyze the data, applying penalized splines (also known as P-splines) to model nonlinear relationships in the confounders. Model selection was done without air pollutants in the models, based on a combination of goodness-of-fit criteria and avoidance of autocorrelation in error terms. Final models included P-splines of time trend, meteorologic data, and influenza epidemics as well as day of the week with an indicator variable. Results are presented as change per interquartile range (IQR), i.e., change in the relative risk of mortality associated with a change in the concentration from the 25th to the 75th percentile of a given pollutant. Air pollutants were considered both as linear terms and as P-splines to assess the exposure-response functions. Changes in effect estimates over time were calculated using fully Bayesian time-varying coefficient models. This method was selected over four other approaches tested in simulation studies. Air-pollution concentrations decreased substantially in Erfurt during the decade under observation. The strongest changes were observed for SO2, for which annual concentrations decreased from 64 microg/m3 in 1992 to 4 microg/m3 in 2001. Concentrations of PM10, PM2.5 (particulate matter with aerodynamic diameter less than or equal to 2.5 microm), and CO decreased by more than 50%. NO2, O3, and ultrafine particles also decreased, though to a lesser extent. Based on visual inspection of the data on the changes in ambient air-pollution concentrations during the study period, we defined three study subperiods: A first subperiod from 1991 to 1995; a second, transitional subperiod from 1995 to 1998; and a third subperiod from 1998 to 2002. Generally, air-pollution concentrations decreased substantially from the first subperiod to the second, and some additional decreases occurred from the second subperiod to the third. During the second, transitional subperiod, natural gas replaced coal as the main energy source in Erfurt. In addition, the number of cars with catalytic converters increased over time, as did the number of cars in general. To facilitate the interpretation of the results, we organized the air pollutants into four groups: (1) NO2, CO, and ultrafine particles, (2) PM10 and PM2.5, (3) SO2, and (4) O3. We observed a 1.6% increased risk for daily mortality (CI, -0.4% to 3.5%) for an increase of 19.7 microg/m3 in NO2 (lag day 3), a 1.9% increased risk (CI, 0.2%-3.6%) for an increase of 0.48 mg/m3 in CO (lag day 4), and a 2.9% increased risk (CI, 0.3%-5.5%) for an increase of 9743/cm3 in ultrafine particles (lag day 4). No consistent associations were observed for PM10, PM2.5, or SO2. For O3, a 4.6% increased risk for daily mortality (CI, 1.1%-8.3%) was associated with a 43.8 microg/m3 maximum 8-hr concentration of O3 per day (lag day 2). For all four pollutants, exposure-response functions suggested no deviation from linearity. However, in time-varying models the strongest associations were observed for NO2, CO, and ultrafine particles during the transition subperiod, from 1995 to 1998, when O3 concentrations were lowest. Changes in source characteristics or ambient air-pollution concentrations were not able to explain these observations in a straightforward manner. However, the observations suggested that changes such as the introduction of three-way catalytic converters in cars and the substitution natural gas for coal might have been beneficial. Overall we concluded that: 1. Economic and political changes and the adoption of new technologies in eastern Germany resulted in distinct improvements in ambient air quality; 2. Urban air pollution in Erfurt changed within one decade from the eastern mixture toward that of western Europe ("western mixture"), which is dominated by concentrations of NOx, O3, fine particles, and ultrafine particles with low concentrations of SO2; 3. There was an association between daily mortality and ultrafine particles and combustion-related gases (lag days 3 or 4); 4. Ultrafine particles seemed to be the best pollution indicator and to point to the role of local combustion in the pollution mixture; 5. Regression coefficients showed variation over time for NO2, CO, ultrafine particles, and O3 that could not be explained by nonlinearity in the exposure-response functions; 6. Mortality associated with pollution was lower at the end of the 1990s than during the 1990s, except for mortality associated with O3; and 7. Mortality associated with pollution was strongest in the second, transitional subperiod, from 1995 to 1998, when changes in source characteristics had taken place but the benefits of improved ambient air quality had not yet been completely achieved.
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