External exposome and all-cause mortality in European cohorts: the EXPANSE project.

Background: Many studies reported associations between long-term exposure to environmental factors and mortality; however, little is known on the combined effects of these factors and health. We aimed to evaluate the association between external exposome and all-cause mortality in large administrative and traditional adult cohorts in Europe. Methods: Data from six administrative cohorts (Catalonia, Greece, Rome, Sweden, Switzerland and the Netherlands, totaling 27,913,545 subjects) and three traditional adult cohorts (CEANS-Sweden, EPIC-NL-the Netherlands, KORA-Germany, totaling 57,653 participants) were included. Multiple exposures were assigned at the residential addresses, and were divided into three a priori defined domains: (1) air pollution [fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC) and warm-season Ozone (warm-O3)]; (2) land/built environment (Normalized Difference Vegetation Index-NDVI, impervious surfaces, and distance to water); (3) air temperature (cold- and warm-season mean and standard deviation). Each domain was synthesized through Principal Component Analysis (PCA), with the aim of explaining at least 80% of its variability. Cox proportional-hazards regression models were applied and the total risk of the external exposome was estimated through the Cumulative Risk Index (CRI). The estimates were adjusted for individual- and area-level covariates. Results: More than 205 million person-years at risk and more than 3.2 million deaths were analyzed. In single-component models, IQR increases of the first principal component of the air pollution domain were associated with higher mortality [HRs ranging from 1.011 (95% CI: 1.005-1.018) for the Rome cohort to 1.076 (1.071-1.081) for the Swedish cohort]. In contrast, lower levels of the first principal component of the land/built environment domain, pointing to reduced vegetation and higher percentage of impervious surfaces, were associated with higher risks. Finally, the CRI of external exposome increased mortality for almost all cohorts. The associations found in the traditional adult cohorts were generally consistent with the results from the administrative ones, albeit without reaching statistical significance. Discussion: Various components of the external exposome, analyzed individually or in combination, were associated with increased mortality across European cohorts. This sets the stage for future research on the connections between various exposure patterns and human health, aiding in the planning of healthier cities.

Long-term exposure to ambient air pollution and inflammatory response in the KORA study.

Previous studies consistently showed an association between fine atmospheric particulate matter (PM2.5) and cardiovascular diseases. Concerns about adverse health effects of ultrafine particles (UFP) are growing but long-term studies are still scarce. In this study, we examined the association between long-term exposure to ambient air pollutants and blood biomarkers of inflammation and coagulation, including fibrinogen, high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA) adiponectin and interleukin-6 (IL-6), measured in the German KORA-S4 cohort study (1999-2001). IL-6 was available for older participants only, who were therefore considered as a subsample. Annual mean concentrations of UFP (as particle number concentration), particulate matter in different particles sizes (PM10, PMcoarse, PM2.5, PM2.5 absorbance), ozone (O3), and nitrogen oxides (NO2, NOX) were estimated by land-use regression models and assigned to participants' home addresses. We performed a multiple linear regression between each pollutant and each biomarker with adjustment for confounders. Per 1 interquartile range (IQR, 1945 particles/cm3) increase of UFP, fibrinogen increased by 0.70 % (0.04; 1.37) and hs-CRP increased by 3.16 % (-0.52; 6.98). Adiponectin decreased by -2.53 % (-4.78; -0.24) per 1 IQR (1.4 µg/m3) increase of PM2.5. Besides, PM2.5 was associated with increased IL-6 in the subsample. In conclusion, we observed that long-term exposure to air pollutants, including both fine and ultrafine particles, was associated with higher concentrations of pro-inflammatory and lower concentrations of an anti-inflammatory blood biomarkers, which is consistent with an increased risk for cardiovascular disease observed for long-term exposure to air pollutants.

Mixtures of long-term exposure to ambient air pollution, built environment and temperature and stroke incidence across Europe.

INTRODUCTION: The complex interplay of multiple environmental factors and cardiovascular has scarcely been studied. Within the EXPANSE project, we evaluated the association between long-term exposure to multiple environmental indices and stroke incidence across Europe. METHODS: Participants from three traditional adult cohorts (Germany, Netherlands and Sweden) and four administrative cohorts (Catalonia [region Spain], Rome [city-wide], Greece and Sweden [nationwide]) were followed until incident stroke, death, migration, loss of follow-up or study end. We estimated exposures at residential addresses from different exposure domains: air pollution (nitrogen dioxide (NO2), particulate matter < 2.5 µm (PM2.5), black carbon (BC), ozone), built environment (green/blue spaces, impervious surfaces) and meteorology (seasonal mean and standard deviation of temperatures). Associations between environmental exposures and stroke were estimated in single and multiple-exposure Cox proportional hazard models, and Principal Component (PC) Analyses derived prototypes for specific exposures domains. We carried out random effects meta-analyses by cohort type. RESULTS: In over 15 million participants, increased levels of NO2 and BC were associated with increased higher stroke incidence in both cohort types. Increased Normalized Difference Vegetation Index (NDVI) was associated with a lower stroke incidence in both cohort types, whereas an increase in impervious surface was associated with an increase in stroke incidence. The first PC of the air pollution domain (PM2.5, NO2 and BC) was associated with an increase in stroke incidence. For the built environment, higher levels of NDVI and lower levels of impervious surfaces were associated with a protective effect [%change in HR per 1 unit = -2.0 (95 %CI, -5.9;2.0) and -1.1(95 %CI, -2.0; -0.3) for traditional adult and administrative cohorts, respectively]. No clear patterns were observed for distance to blue spaces or temperature parameters. CONCLUSIONS: We observed increased HRs for stroke with exposure to PM2.5, NO2 and BC, lower levels of greenness and higher impervious surface in single and combined exposure models.

Disentangling associations between multiple environmental exposures and all-cause mortality: an analysis of European administrative and traditional cohorts.

Background: We evaluated the independent and joint effects of air pollution, land/built environment characteristics, and ambient temperature on all-cause mortality as part of the EXPANSE project. Methods: We collected data from six administrative cohorts covering Catalonia, Greece, the Netherlands, Rome, Sweden, and Switzerland and three traditional cohorts in Sweden, the Netherlands, and Germany. Participants were linked to spatial exposure estimates derived from hybrid land use regression models and satellite data for: air pollution [fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3)], land/built environment [normalized difference vegetation index (NDVI), distance to water, impervious surfaces], and ambient temperature (the mean and standard deviation of warm and cool season temperature). We applied Cox proportional hazard models accounting for several cohort-specific individual and area-level variables. We evaluated the associations through single and multiexposure models, and interactions between exposures. The joint effects were estimated using the cumulative risk index (CRI). Cohort-specific hazard ratios (HR) were combined using random-effects meta-analyses. Results: We observed over 3.1 million deaths out of approximately 204 million person-years. In administrative cohorts, increased exposure to PM2.5, NO2, and BC was significantly associated with all-cause mortality (pooled HRs: 1.054, 1.033, and 1.032, respectively). We observed an adverse effect of increased impervious surface and mean season-specific temperature, and a protective effect of increased O3, NDVI, distance to water, and temperature variation on all-cause mortality. The effects of PM2.5 were higher in areas with lower (10th percentile) compared to higher (90th percentile) NDVI levels [pooled HRs: 1.054 (95% confidence interval (CI) 1.030-1.079) vs. 1.038 (95% CI 0.964-1.118)]. A similar pattern was observed for NO2. The CRI of air pollutants (PM2.5 or NO2) plus NDVI and mean warm season temperature resulted in a stronger effect compared to single-exposure HRs: [PM2.5 pooled HR: 1.061 (95% CI 1.021-1.102); NO2 pooled HR: 1.041 (95% CI 1.025-1.057)]. Non-significant effects of similar patterns were observed in traditional cohorts. Discussion: The findings of our study not only support the independent effects of long-term exposure to air pollution and greenness, but also highlight the increased effect when interplaying with other environmental exposures.

Short-term effects of ultrafine particles on heart rate variability: A systematic review and meta-analysis.

An increasing number of epidemiological studies have examined the association between ultrafine particles (UFP) and imbalanced autonomic control of the heart, a potential mechanism linking particulate matter air pollution to cardiovascular disease. This study systematically reviews and meta-analyzes studies on short-term effects of UFP on autonomic function, as assessed by heart rate variability (HRV). We searched PubMed and Web of Science for articles published until June 30, 2022. We extracted quantitative measures of UFP effects on HRV with a maximum lag of 15 days from single-pollutant models. We assessed the risk of bias in the included studies regarding confounding, selection bias, exposure assessment, outcome measurement, missing data, and selective reporting. Random-effects models were applied to synthesize effect estimates on HRV of various time courses. Twelve studies with altogether 1,337 subjects were included in the meta-analysis. For an increase of 10,000 particles/cm3 in UFP assessed by central outdoor measurements, our meta-analysis showed immediate decreases in the standard deviation of the normal-to-normal intervals (SDNN) by 4.0% [95% confidence interval (CI): 7.1%, -0.9%] and root mean square of successive R-R interval differences (RMSSD) by 4.7% (95% CI: 9.1%, 0.0%) within 6 h after exposure. The immediate decreases in SDNN and RMSSD associated with UFP assessed by personal measurements were smaller and borderline significant. Elevated UFP were also associated with decreases in SDNN, low-frequency power, and the ratio of low-frequency to high-frequency power when pooling estimates of lags across hours to days. We did not find associations between HRV and concurrent-day UFP exposure (daily average of at least 18 h) or exposure at lags ≥ one day. Our study indicates that short-term exposure to ambient UFP is associated with decreased HRV, predominantly as an immediate response within hours. This finding highlights that UFP may contribute to the onset of cardiovascular events through autonomic dysregulation.

Low emission zones reduced PM10 but not NO2 concentrations in Berlin and Munich, Germany.

Low emission zones (LEZs) aiming at improving the air quality in urban areas have been implemented in many European cities. However, studies are limited in evaluating the effects of LEZ, and most of which used simple methods. In this study, a general additive mixed model was utilized to account for confounders in the atmosphere and validate the effects of LEZ on PM10 and NO2 concentrations in two German cities. In addition, the effects of LEZ on elemental carbon (EC) and total carbon (TC) in Berlin were also evaluated. The LEZ effects were estimated after taking into account air pollutant concentrations at a reference site located in the regional background, and adjusting for hour of the week, public holidays, season, and wind direction. The LEZ in Berlin, and the LEZ in combination with the heavy-duty vehicle (HDV) transit ban in Munich significantly reduced the PM10 concentrations, at both traffic sites (TS) and urban background sites (UB). The effects were greater in LEZ stage 3 than in LEZ stages 2 and 1. Moreover, compared with PM10, LEZ was more efficient in reducing EC, a component that is considered more toxic than PM10 mass. In contrast, the LEZ had no consistent effect on NO2 levels: no effects were observed in Berlin; in Munich, the combination of the LEZ and the HDV transit ban reduced NO2 at UB site in LEZ stage 1, but without further reductions in subsequent stages of the LEZ. Overall, our study indicated that LEZs, which target the major primary air pollution source in the highly populated city center could be an effective way to improve urban air quality such as PM mass concentration and EC level.

Longitudinal associations between ambient air pollution and insulin sensitivity: results from the KORA cohort study.

BACKGROUND: Impaired insulin sensitivity could be an intermediate step that links exposure to air pollution to the development of type 2 diabetes. However, longitudinal associations of air pollution with insulin sensitivity remain unclear. Our study investigated the associations of long-term air pollution exposure with the degree and rate of change of insulin sensitivity. METHODS: In this longitudinal study, we analysed data from the Cooperative Health Research in the Region of Augsburg (KORA) cohort from Augsburg, Germany, which recruited participants aged 25-74 years in the survey between 1999 and 2001 (KORA S4), with two follow-up examinations in 2006-08 (KORA F4) and 2013-14 (KORA FF4). Serum concentrations of fasting insulin and glucose, and homoeostasis model assessment of insulin resistance (HOMA-IR, a surrogate measure of insulin sensitivity) and ß-cell function (HOMA-B, a surrogate marker for fasting insulin secretion) were assessed at up to three visits between 1999 and 2014. Annual average air pollutant concentrations at the residence were estimated by land-use regression models. We examined the associations of air pollution with repeatedly assessed biomarker levels using mixed-effects models, and we assessed the associations with the annual rate of change in biomarkers using quantile regression models. FINDINGS: Among 9620 observations from 4261 participants in the KORA cohort, we included 6008 (62·5%) observations from 3297 (77·4%) participants in our analyses. Per IQR increment in annual average air pollutant concentrations, HOMA-IR significantly increased by 2·5% (95% CI 0·3 to 4·7) for coarse particulate matter, by 3·1% (0·9 to 5·3) for PM2·5, by 3·6% (1·0 to 6·3) for PM2·5absorbance, and by 3·2% (0·6 to 5·8) for nitrogen dioxide, and borderline significantly increased by 2·2% (-0·1 to 4·5) for ozone, whereas it did not significantly increase for the whole range of ultrafine particles. Similar positive associations in slightly smaller magnitude were observed for HOMA-B and fasting insulin levels. In addition, air pollutant concentrations were positively associated with the annual rate of change in HOMA-IR, HOMA-B, and fasting insulin. Neither the level nor the rate of change of fasting glucose were associated with air pollution exposure. INTERPRETATION: Our study indicates that long-term air pollution exposure could contribute to the development of insulin resistance, which is one of the key factors in the pathogenesis of type 2 diabetes. FUNDING: German Federal Ministry of Education and Research.

Association of Long-Term Air Pollution with Prevalence and Incidence of Distal Sensorimotor Polyneuropathy: KORA F4/FF4 Study.

BACKGROUND: Air pollution contributes to type 2 diabetes and cardiovascular diseases, but its relevance for other complications of diabetes, in particular distal sensorimotor polyneuropathy (DSPN), is unclear. Recent studies have indicated that DSPN is also increasingly prevalent in obesity. OBJECTIVES: We aimed to assess associations of air pollutants with prevalent and incident DSPN in a population-based study of older individuals with high rates of type 2 diabetes and obesity. METHODS: Cross-sectional analyses on prevalent DSPN were based on 1,075 individuals 62-81 years of age from the German Cooperative Health Research in the Region of Augsburg (KORA) F4 survey (2006-2008). Analyses on incident DSPN included 424 individuals without DSPN at baseline (KORA F4), of whom 188 had developed DSPN by the KORA FF4 survey (2013-2014). Associations of annual average air pollutant concentrations at participants' residences with prevalent and incident DSPN were estimated using Poisson regression models with a robust error variance adjusting for multiple confounders. RESULTS: Higher particle number concentrations (PNCs) were associated with higher prevalence [risk ratio (RR) per interquartile range (IQR) increase=1.10 (95% CI: 1.01, 1.20)] and incidence [1.11 (95% CI: 0.99, 1.24)] of DSPN. In subgroup analyses, particulate (PNC, PM10, PMcoarse, PM2.5, and PM2.5abs) and gaseous (NOx, NO2) pollutants were positively associated with prevalent DSPN in obese participants, whereas corresponding estimates for nonobese participants were close to the null [e.g., for an IQR increase in PNC, RR=1.17 (95% CI: 1.05, 1.31) vs. 1.06 (95% CI: 0.95, 1.19); pinteraction=0.22]. With the exception of PM2.5abs, corresponding associations with incident DSPN were positive in obese participants but null or inverse for nonobese participants, with pinteraction≤0.13 [e.g., for PNC, RR=1.28 (95% CI: 1.08, 1.51) vs. 1.03 (95% CI: 0.90, 1.18); pinteraction=0.03]. DISCUSSION: Both particulate and gaseous air pollutants were positively associated with prevalent and incident DSPN in obese individuals. Obesity and air pollution may have synergistic effects on the development of DSPN. https://doi.org/10.1289/EHP7311.

Meta-analysis on short-term exposure to ambient ultrafine particles and respiratory morbidity.

AIM: There is growing interest in the health effects following exposure to ambient particles with a diameter <100 nm defined as ultrafine particles (UFPs), although studies so far have reported inconsistent results. We have undertaken a systematic review and meta-analysis for respiratory hospital admissions and emergency room visits following short-term exposure to UFPs. METHODS: We searched PubMed and the Web of Science for studies published up to March 2019 to update previous reviews. We applied fixed- and random-effects models, assessed heterogeneity between cities and explored possible effect modifiers. RESULTS: We identified nine publications, reporting effects from 15 cities, 11 of which were European. There was great variability in exposure assessment, outcome measures and the exposure lags considered. Our meta-analyses did not support UFP effects on respiratory morbidity across all ages. We found consistent statistically significant associations following lag 2 exposure during the warm period and in cities with mean daily UFP concentrations <6000 particles·cm‒3, which was approximately the median of the city-specific mean levels. Among children aged 0-14 years, a 10 000 particle·cm‒3 increase in UFPs 2 or 3 days before was associated with a relative risk of 1.01 (95% CI 1.00-1.02) in respiratory hospital admissions. CONCLUSIONS: Our study indicates UFP effects on respiratory health among children, and during the warm season across all ages at longer lags. The limited evidence and the large heterogeneity of previous reports call for future exposure assessment harmonisation and expanded research.

[Combined effects of different environmental factors on health: air pollution, temperature, green spaces, pollen, and noise]. / Kombinierte Effekte verschiedener Umweltfaktoren auf die Gesundheit: Luftschadstoffe, Temperatur, Grünflächen, Pollen und Lärm.

Environmental factors affect the health and wellbeing of urban residents. However, they do not act individually on humans, but instead show potential synergistic or antagonistic effects. Questions that arise from this are: How does a combination of air pollutants with other environmental factors impact health? How well are these associations evidenced? What methods can we use to look at them? In this article, methodical approaches regarding the effects of a combination of various environmental factors are first described. Environmental factors are then examined, which together with different air pollutants, have an impact on human health such as ambient temperature, noise, and pollen as well as the effect of green spaces. Physical activity and nutrition are addressed regarding the attenuation of health effects from air pollution.While there is often clear evidence of health effects of single environmental stressors, there are still open questions in terms of their interaction. The research methods required for this still need to be further developed. The interrelationship between the different environmental factors make it clear that (intervention) measures for reducing single indicators are also interlinked. Regarding traffic, switching from passive to active transport (e.g., due to safe cycle paths and other measures) leads to less air pollutants, smaller increases in temperature in the long term, and at the same time improved health of the individual. As a result, sensible planning of the built environment has great potential to reduce environmental stressors and improve people's health and wellbeing.