Long-Term Safety and Clinical Outcomes with Insulin Degludec/Insulin Aspart Treatment in Japanese Patients with Diabetes: A Real-World, Prospective, Observational Study.

INTRODUCTION: Insulin degludec/insulin aspart (IDegAsp) provides effective glycaemic control with an acceptable safety profile in Japanese patients with diabetes in randomised clinical trials. This post-marketing surveillance study assessed long-term safety and clinical outcomes with IDegAsp in a Japanese real-world setting. METHODS: Multicentre, prospective, observational, open-label, single-arm study of Japanese patients with diabetes requiring insulin therapy, who had switched to IDegAsp at their treating physician's discretion in clinical practice. One year after initiating IDegAsp, incidence of adverse events (AEs [primary endpoint]), serious AEs, adverse drug reactions (ADRs), and severe hypoglycaemia (secondary safety endpoints) were assessed in the safety analysis set (SAS). Secondary effectiveness endpoints were change from baseline in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in the effectiveness analysis set (EAS). RESULTS: Overall, 1321 patients were included (SAS, n = 1321; EAS, n = 1285); 4.2% with type 1 diabetes, 95.2% with type 2 diabetes, 0.7% with other/unknown diabetes type. In total, 204 AEs were reported in 132 patients (10.0% of the SAS), at a rate [95% confidence interval (CI)] of 16.2 events/100 patient-years of exposure (PYE) [14.0; 18.4]. By preferred term, 'hypoglycaemia' was the most frequent AE (45 events in 31 patients [2.3%]; rate [95% CI] 3.6 events/100 PYE [2.5; 4.6]). Serious AEs occurred in 4.2% of patients (rate [95% CI] 5.7 events/100 PYE [4.4; 7.0]), and ADRs in 3.1% (rate [95% CI] 4.6 reactions/100 PYE [3.4; 5.8]). Six events of severe hypoglycaemia were reported in five patients (0.4%; rate [95% CI] 0.5 events/100 PYE [0.1; 0.9]). Change from baseline to 1 year was - 0.51% and - 32.1 mg/dL for HbA1c and FPG, respectively (P < 0.0001 for both). CONCLUSION: In Japanese patients with diabetes, initiation of IDegAsp in real-world clinical practice was well tolerated, with no new safety signals, and associated with improved glycaemic control after 1 year. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02821052.

CAPTURE: a multinational, cross-sectional study of cardiovascular disease prevalence in adults with type 2 diabetes across 13 countries.

BACKGROUND: There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials. METHODS: Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters. RESULTS: The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6-17.9 years) and glycated hemoglobin 7.3% (6.6-8.4%) [56 mmol/mol (49-68 mmol/mol)]. Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval [CI] 32.7-36.8) and 31.8% (95% CI 29.7-33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively. CONCLUSIONS: In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019).

Body mass index and risk of obesity-related conditions in a cohort of 2.9 million people: Evidence from a UK primary care database.

OBJECTIVE: Obesity rates in the United Kingdom are some of the highest in Western Europe, with considerable clinical and societal impacts. Obesity is associated with type 2 diabetes (T2D), osteoarthritis, cardiovascular disease, and increased mortality; however, relatively few studies have examined the occurrence of multiple obesity-related outcomes in the same patient population. This study was designed to examine the associations between body mass index (BMI) and a broad range of obesity-related conditions in the same large cohort from a UK-representative primary care database. METHODS: Demographic data and diagnosis codes were extracted from the Clinical Practice Research Datalink GOLD database in January 2019. Adults registered for ≥ 3 years were grouped by BMI, with BMI 18.5-24.9 kg/m2 as reference group. Associations between BMI and 12 obesity-related outcomes were estimated using Cox proportional hazard models, adjusted for age, sex, and smoking. RESULTS: More than 2.9 million individuals were included in the analyses and were followed up for occurrence of relevant outcomes for a median of 11.4 years during the study period. Generally, there was a stepwise increase in risk of all outcomes with higher BMI. Individuals with BMI 40.0-45.0 kg/m2 were at particularly high risk of sleep apnea (hazard ratio [95% confidence interval] vs. reference group: 19.8 [18.9-20.8]), T2D (12.4 [12.1-12.7]), heart failure (3.46 [3.35-3.57]), and hypertension (3.21 [3.15-3.26]). CONCLUSIONS: This study substantiates evidence linking higher BMI to higher risk of a range of serious health conditions, in a large, representative UK cohort. By focusing on obesity-related conditions, this demonstrates the wider clinical impact and the healthcare burden of obesity, and highlights the vital importance of management, treatment approaches, and public health programs to mitigate the impact of this disease.

Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts.

BACKGROUND: Ambient air pollution contains low concentrations of carcinogens implicated in the etiology of urinary bladder cancer (BC). Little is known about whether exposure to air pollution influences BC in the general population. OBJECTIVE: To evaluate the association between long-term exposure to ambient air pollution and BC incidence. DESIGN, SETTING, AND PARTICIPANTS: We obtained data from 15 population-based cohorts enrolled between 1985 and 2005 in eight European countries (N=303431; mean follow-up 14.1 yr). We estimated exposure to nitrogen oxides (NO2 and NOx), particulate matter (PM) with diameter <10µm (PM10), <2.5µm (PM2.5), between 2.5 and 10µm (PM2.5-10), PM2.5absorbance (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and meta-analyses to estimate summary hazard ratios (HRs) for BC incidence. RESULTS AND LIMITATIONS: During follow-up, 943 incident BC cases were diagnosed. In the meta-analysis, none of the exposures were associated with BC risk. The summary HRs associated with a 10-µg/m3 increase in NO2 and 5-µg/m3 increase in PM2.5 were 0.98 (95% confidence interval [CI] 0.89-1.08) and 0.86 (95% CI 0.63-1.18), respectively. Limitations include the lack of information about lifetime exposure. CONCLUSIONS: There was no evidence of an association between exposure to outdoor air pollution levels at place of residence and risk of BC. PATIENT SUMMARY: We assessed the link between outdoor air pollution at place of residence and bladder cancer using the largest study population to date and extensive assessment of exposure and comprehensive data on personal risk factors such as smoking. We found no association between the levels of outdoor air pollution at place of residence and bladder cancer risk.

Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE).

Background: Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent. Methods: In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5, PM10, and PMcoarse), PM2.5 absorbance, nitrogen oxides (NO2 and NOx) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. Results: Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89-3.14 per 10-5/m3), and weak positive or null associations with the other pollutants. Hazard ratio for PM2.5 absorbance (1.01; 0.38-2.71 per 10-5/m3) and all other pollutants were lower for nonmalignant than for malignant brain tumors. Conclusion: We found suggestive evidence of an association between long-term exposure to PM2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.

Long-Term Exposure to Ambient Air Pollution and Incidence of Postmenopausal Breast Cancer in 15 European Cohorts within the ESCAPE Project.

BACKGROUND: Epidemiological evidence on the association between ambient air pollution and breast cancer risk is inconsistent. OBJECTIVE: We examined the association between long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in European women. METHODS: In 15 cohorts from nine European countries, individual estimates of air pollution levels at the residence were estimated by standardized land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE) and Transport related Air Pollution and Health impacts ­ Integrated Methodologies for Assessing Particulate Matter (TRANSPHORM) projects: particulate matter (PM) ≤2.5µm, ≤10µm, and 2.5­10µm in diameter (PM2.5, PM10, and PMcoarse, respectively); PM2.5 absorbance; nitrogen oxides (NO2 and NOx); traffic intensity; and elemental composition of PM. We estimated cohort-specific associations between breast cancer and air pollutants using Cox regression models, adjusting for major lifestyle risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. RESULTS: Of 74,750 postmenopausal women included in the study, 3,612 developed breast cancer during 991,353 person-years of follow-up. We found positive and statistically insignificant associations between breast cancer and PM2.5 {hazard ratio (HR)=1.08 [95% confidence interval (CI): 0.77, 1.51] per 5 µg/m3}, PM10 [1.07 (95% CI: 0.89, 1.30) per 10 µg/m3], PMcoarse[1.20 (95% CI: 0.96, 1.49 per 5 µg/m3], and NO2 [1.02 (95% CI: 0.98, 1.07 per 10 µg/m3], and a statistically significant association with NOx [1.04 (95% CI: 1.00, 1.08) per 20 µg/m3, p=0.04]. CONCLUSIONS: We found suggestive evidence of an association between ambient air pollution and incidence of postmenopausal breast cancer in European women. https://doi.org/10.1289/EHP1742.

Ambient air pollution and primary liver cancer incidence in four European cohorts within the ESCAPE project.

BACKGROUND: Tobacco smoke exposure increases the risk of cancer in the liver, but little is known about the possible risk associated with exposure to ambient air pollution. OBJECTIVES: We evaluated the association between residential exposure to air pollution and primary liver cancer incidence. METHODS: We obtained data from four cohorts with enrolment during 1985-2005 in Denmark, Austria and Italy. Exposure to nitrogen oxides (NO2 and NOX), particulate matter (PM) with diameter of less than 10µm (PM10), less than 2.5µm (PM2.5), between 2.5 and 10µm (PM2.5-10) and PM2.5 absorbance (soot) at baseline home addresses were estimated using land-use regression models from the ESCAPE project. We also investigated traffic density on the nearest road. We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and random-effects meta-analyses to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Out of 174,770 included participants, 279 liver cancer cases were diagnosed during a mean follow-up of 17 years. In each cohort, HRs above one were observed for all exposures with exception of PM2.5 absorbance and traffic density. In the meta-analysis, all exposures were associated with elevated HRs, but none of the associations reached statistical significance. The summary HR associated with a 10-µg/m3 increase in NO2 was 1.10 (95% confidence interval (CI): 0.93, 1.30) and 1.34 (95% CI: 0.76, 2.35) for a 5-µg/m3 increase in PM2.5. CONCLUSIONS: The results provide suggestive evidence that ambient air pollution may increase the risk of liver cancer. Confidence intervals for associations with NO2 and NOX were narrower than for the other exposures.

Urinary Cadmium and Breast Cancer: A Prospective Danish Cohort Study.

Background: Cadmium is a human lung carcinogen, and recent evidence suggests it may play a role in hormone-related cancers because of its estrogenic activity. Case-control studies consistently show higher cadmium concentrations in urine from women diagnosed with breast cancer compared with control women. Our aim was to investigate the association between urinary cadmium and breast cancer in a prospective design. Methods: We conducted a case-cohort study using the population-based Danish Diet Cancer and Health Cohort. Women age 50 to 64 years were recruited in 1993-1997 and provided urine for analysis. We identified 900 incident case patients in the Danish Cancer Registry and compared with 898 individuals in a subcohort. Urine samples collected at enrollment into the cohort were analyzed for cadmium and creatinine. We estimated incidence rate ratios (IRRs) for breast cancer in Cox proportional hazards models with age as time axis and calculated 95% confidence intervals (CIs). Results: The linear analysis showed no association between urinary cadmium and risk for breast cancer (IRR = 1.00, 95% CI = 0.81 to 1.24 per ng Cd/mL urine). The categorical analyses showed a slightly higher risk for breast cancer for the second (IRR = 1.10, 95% CI = 0.86 to 1.42) and third (IRR = 1.14, 95% CI = 0.83 to 1.55) exposure tertiles compared with the lowest tertile. Results were similar in analyses of breast cancer subtypes defined by estrogen and progesterone receptor status and by histology, and analyses stratified by years from baseline to diagnosis. Conclusions: This large prospective study showed no association between urinary concentration of cadmium and subsequent risk for development of postmenopausal breast cancer.

Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts.

Several studies have indicated weakly increased risk for kidney cancer among occupational groups exposed to gasoline vapors, engine exhaust, polycyclic aromatic hydrocarbons and other air pollutants, although not consistently. It was the aim to investigate possible associations between outdoor air pollution at the residence and the incidence of kidney parenchyma cancer in the general population. We used data from 14 European cohorts from the ESCAPE study. We geocoded and assessed air pollution concentrations at baseline addresses by land-use regression models for particulate matter (PM10 , PM2.5 , PMcoarse , PM2.5 absorbance (soot)) and nitrogen oxides (NO2 , NOx ), and collected data on traffic. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses to calculate summary hazard ratios (HRs). The 289,002 cohort members contributed 4,111,908 person-years at risk. During follow-up (mean 14.2 years) 697 incident cancers of the kidney parenchyma were diagnosed. The meta-analyses showed higher HRs in association with higher PM concentration, e.g. HR = 1.57 (95%CI: 0.81-3.01) per 5 µg/m3 PM2.5 and HR = 1.36 (95%CI: 0.84-2.19) per 10-5 m-1 PM2.5 absorbance, albeit never statistically significant. The HRs in association with nitrogen oxides and traffic density on the nearest street were slightly above one. Sensitivity analyses among participants who did not change residence during follow-up showed stronger associations, but none were statistically significant. Our study provides suggestive evidence that exposure to outdoor PM at the residence may be associated with higher risk for kidney parenchyma cancer; the results should be interpreted cautiously as associations may be due to chance.

Exposure to Ambient Air Pollution and the Risk of Inflammatory Bowel Disease: A European Nested Case-Control Study.

BACKGROUND: Industrialization has been linked to the etiology of inflammatory bowel disease (IBD). AIM: We investigated the association between air pollution exposure and IBD. METHODS: The European Prospective Investigation into Cancer and Nutrition cohort was used to identify cases with Crohn's disease (CD) (n = 38) and ulcerative colitis (UC) (n = 104) and controls (n = 568) from Denmark, France, the Netherlands, and the UK, matched for center, gender, age, and date of recruitment. Air pollution data were obtained from the European Study of Cohorts for Air Pollution Effects. Residential exposure was assessed with land-use regression models for particulate matter with diameters of <10 µm (PM10), <2.5 µm (PM2.5), and between 2.5 and 10 µm (PMcoarse), soot (PM2.5 absorbance), nitrogen oxides, and two traffic indicators. Conditional logistic regression analyses were performed to calculate odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: Although air pollution was not significantly associated with CD or UC separately, the associations were mostly similar. Individuals with IBD were less likely to have higher exposure levels of PM2.5 and PM10, with ORs of 0.24 (95 % CI 0.07-0.81) per 5 µg/m(3) and 0.25 (95 % CI 0.08-0.78) per 10 µg/m(3), respectively. There was an inverse but nonsignificant association for PMcoarse. A higher nearby traffic load was positively associated with IBD [OR 1.60 (95 % CI 1.04-2.46) per 4,000,000 motor vehicles × m per day]. Other air pollutants were positively but not significantly associated with IBD. CONCLUSION: Exposure to air pollution was not found to be consistently associated with IBD.

Exposure to long-term air pollution and road traffic noise in relation to cholesterol: A cross-sectional study.

BACKGROUND: Exposure to traffic noise and air pollution have both been associated with cardiovascular disease, though the mechanisms behind are not yet clear. OBJECTIVES: We aimed to investigate whether the two exposures were associated with levels of cholesterol in a cross-sectional design. METHODS: In 1993­1997, 39,863 participants aged 50­64 year and living in the Greater Copenhagen area were enrolled in a population-based cohort study. For each participant, non-fasting total cholesterol was determined in whole blood samples on the day of enrolment. Residential addresses 5-years preceding enrolment were identified in a national register and road traffic noise (Lden) were modeled for all addresses. For air pollution, nitrogen dioxide (NO2) was modeled at all addresses using a dispersion model and PM2.5 was modeled at all enrolment addresses using a land-use regression model. Analyses were done using linear regression with adjustment for potential confounders as well as mutual adjustment for the three exposures. RESULTS: Baseline residential exposure to the interquartile range of road traffic noise,NO2 and PM2.5 was associated with a 0.58 mg/dl (95% confidence interval: −0.09; 1.25), a 0.68 mg/dl (0.22; 1.16) and a 0.78 mg/dl (0.22; 1.34) higher level of total cholesterol in single pollutant models, respectively. In two pollutant models with adjustment for noise in air pollution models and vice versa, the association between air pollution and cholesterol remained for both air pollution variables (NO2: 0.72 (0.11; 1.34); PM2.5: 0.70 (0.12; 1.28) mg/dl), whereas there was no association for noise (−0.08mg/dl). In three-pollutant models (NO2, PM2.5 and road traffic noise), estimates for NO2 and PM2.5 were slightly diminished (NO2: 0.58 (−0.05; 1.22); PM2.5: 0.57 (−0.02; 1.17) mg/dl). CONCLUSIONS: Air pollution and possibly also road traffic noise may be associated with slightly higher levels of cholesterol, though associations for the two exposures were difficult to separate.

Dietary Intake Estimates and Urinary Cadmium Levels in Danish Postmenopausal Women.

BACKGROUND: Cadmium is a known carcinogen that can disrupt endocrine signalling. Cigarette smoking and food are the most common routes of non-occupational exposure to cadmium. Cadmium accumulates in the kidney and can be measured in urine, making urine cadmium (U-Cd) a biomarker of long-term exposure. However dietary-cadmium (D-Cd) intake estimates are often used as surrogate indicator of cadmium exposure in non-smoking subjects. It is therefore important to investigate the concordance between D-Cd estimates obtained with Food Frequency Questionnaires and U-Cd. METHODS: U-Cd levels were compared with estimated dietary-cadmium (D-Cd) intake in 1764 post-menopausal women from the Danish Diet, Cancer and Health cohort. For each participant, a food frequency questionnaire, and measures of cadmium content in standard recipes were used to judge the daily intake of cadmium, normalized by daily caloric intake. Cadmium was measured by ICP-MS in spot urine sampled at baseline and normalized by urinary creatinine. Information on diet, socio-demographics and smoking were self-reported at baseline. RESULTS: Linear regressions between U-Cd and D-Cd alone revealed minimal but significant positive correlation in never smokers (R2 = 0.0076, ß = 1.5% increase per 1 ng Cd kcal(-1), p = 0.0085, n = 782), and negative correlation in current smokers (R2 = 0.0184, ß = 7.1% decrease per 1 ng Cd kcal(-1) change, p = 0.0006, n = 584). In the full study population, most of the variability in U-Cd was explained by smoking status (R2 = 0.2450, n = 1764). A forward selection model revealed that the strongest predictors of U-Cd were age in never smokers (Δ R2 = 0.04), smoking duration in former smokers (Δ R2 = 0.06) and pack-years in current smokers (Δ R2 = 0.07). Food items that contributed to U-Cd were leafy vegetables and soy-based products, but explained very little of the variance in U-Cd. CONCLUSIONS: Dietary-Cd intake estimated from food frequency questionnaires correlates only minimally with U-Cd biomarker, and its use as a Cd exposure indicator may be of limited utility in epidemiologic studies.

Residential Exposure to Road and Railway Noise and Risk of Prostate Cancer: A Prospective Cohort Study.

BACKGROUND: Few modifiable risk factors for prostate cancer are known. Recently, disruption of the circadian system has been proposed to affect risk, as it entails an inhibited melatonin production, and melatonin has demonstrated beneficial effects on cancer inhibition. This suggests a potential role of traffic noise in prostate cancer. METHODS: Road traffic and railway noise was calculated for all present and historical addresses from 1987-2010 for a cohort of 24,473 middle-aged, Danish men. During follow-up, 1,457 prostate cancer cases were identified. We used Cox Proportional Hazards Models to calculate the association between noise exposure and incident prostate cancer. Incidence Rate Ratios (IRR) were calculated as crude and adjusted for smoking status, education, socioeconomic position, BMI, waist circumference, physical activity, calendar year, and traffic noise from other sources than the one investigated. RESULTS: There was no association between residential road traffic noise and risk of prostate cancer for any of the three exposure windows: 1, 5 or 10-year mean noise exposure before prostate cancer diagnosis. This result persisted when stratifying cases by aggressiveness. For railway noise, there was no association with overall prostate cancer. There was no statistically significant effect modification by age, education, smoking status, waist circumference or railway noise, on the association between road traffic noise and prostate cancer, although there seemed to be a suggestion of an association among never smokers (IRR: 1.16; 95% CI: 1.00-1.36). CONCLUSION: The present study does not support an overall association between either railway or road traffic noise and overall prostate cancer.

Long-term Exposure to Particulate Matter Constituents and the Incidence of Coronary Events in 11 European Cohorts.

BACKGROUND: Long-term exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity and mortality but little is known about the role of the chemical composition of PM. This study examined the association of residential long-term exposure to PM components with incident coronary events. METHODS: Eleven cohorts from Finland, Sweden, Denmark, Germany, and Italy participated in this analysis. 5,157 incident coronary events were identified within 100,166 persons followed on average for 11.5 years. Long-term residential concentrations of PM < 10 µm (PM10), PM < 2.5 µm (PM2.5), and a priori selected constituents (copper, iron, nickel, potassium, silicon, sulfur, vanadium, and zinc) were estimated with land-use regression models. We used Cox proportional hazard models adjusted for a common set of confounders to estimate cohort-specific component effects with and without including PM mass, and random effects meta-analyses to pool cohort-specific results. RESULTS: A 100 ng/m³ increase in PM10 K and a 50 ng/m³ increase in PM2.5 K were associated with a 6% (hazard ratio and 95% confidence interval: 1.06 [1.01, 1.12]) and 18% (1.18 [1.06, 1.32]) increase in coronary events. Estimates for PM10 Si and PM2.5 Fe were also elevated. All other PM constituents indicated a positive association with coronary events. When additionally adjusting for PM mass, the estimates decreased except for K. CONCLUSIONS: This multicenter study of 11 European cohorts pointed to an association between long-term exposure to PM constituents and coronary events, especially for indicators of road dust.

Dietary cadmium intake and risk of prostate cancer: a Danish prospective cohort study.

BACKGROUND: Cadmium is classified as a human lung carcinogen based on evidence from high-exposure occupational settings. Though cadmium has no physiological role, increasing evidence suggests cadmium may mimic steroid hormones. This dual ability of being carcinogenic and hormone-like makes cadmium a concern for hormone-related cancers. Causes of prostate cancer are not clear, but steroid hormones, particularly androgens and probably estrogens, may be involved. Cadmium has been positively associated with prostate cancer in occupationally exposed men. In non-occupationally exposed populations, diet and smoking are the main sources of cadmium exposure. The aim of this study was to investigate the association between dietary cadmium intake and prostate cancer risk in Danish men. METHODS: Dietary cadmium intake was estimated in the Danish Diet, Cancer and Health cohort at baseline 1993-97. The estimates were based on a 192 item semi-quantitative food frequency questionnaire and cadmium contents in all food items. Among 26,778 men we identified 1,567 prostate cancer cases from baseline through December 31, 2010 using the Danish Cancer Registry. The association between dietary cadmium intake and prostate cancer risk was analysed using Cox regression models. RESULTS: We did not find an association between dietary cadmium intake and prostate cancer risk (adjusted incidence rate ratio per 10 µg day(-1) = 0.98 (95% CI = 0.88-1.10)). The association did not differ according to aggressiveness of prostate cancer. Educational level, smoking status, BMI, zinc or iron intake did not modify the association. CONCLUSIONS: In our study, we did not find an association between dietary cadmium intake and prostate cancer risk in a cohort of Danish men.

Development of land use regression models for elemental, organic carbon, PAH, and hopanes/steranes in 10 ESCAPE/TRANSPHORM European study areas.

Land use regression (LUR) models have been used to model concentrations of mainly traffic-related air pollutants (nitrogen oxides (NOx), particulate matter (PM) mass or absorbance). Few LUR models are published of PM composition, whereas the interest in health effects related to particle composition is increasing. The aim of our study was to evaluate LUR models of polycyclic aromatic hydrocarbons (PAH), hopanes/steranes, and elemental and organic carbon (EC/OC) content of PM2.5. In 10 European study areas, PAH, hopanes/steranes, and EC/OC concentrations were measured at 16-40 sites per study area. LUR models for each study area were developed on the basis of annual average concentrations and predictor variables including traffic, population, industry, natural land obtained from geographic information systems. The highest median model explained variance (R(2)) was found for EC - 84%. The median R(2) was 51% for OC, 67% for benzo[a]pyrene, and 38% for sum of hopanes/steranes, with large variability between study areas. Traffic predictors were included in most models. Population and natural land were included frequently as additional predictors. The moderate to high explained variance of LUR models and the overall moderate correlation with PM2.5 model predictions support the application of especially the OC and PAH models in epidemiological studies.

Dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal women: a prospective cohort study.

PURPOSE: Cadmium is a human lung carcinogen and possesses estrogen-like activity. This combination of carcinogenic and estrogenic activity makes cadmium a contaminant of high concern for hormone-related cancers. Diet and smoking are the main sources of cadmium exposure. The aim of this study was to investigate the association between dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal woman. METHODS: We estimated dietary cadmium intake in the Diet, Cancer and Health cohort at enrolment 1993-97. The estimates were based on food frequency questionnaires and cadmium contents in all foods. Among 23,815 postmenopausal women we identified 1390 breast, 192 endometrial, and 146 ovarian cancer cases from enrolment through December 31, 2010 using the Danish Cancer Registry. Cox regression was used to analyse the association between dietary cadmium intake and cancer risk. RESULTS: Mean dietary cadmium intake was 14 µg/day. Cadmium was not associated with breast cancer, incidence rate ratio (IRR) = 0.99, 95% confidence interval (CI): 0.87-1.13 per 10 µg higher dietary cadmium intake/day; endometrial cancer, IRR = 1.08, 95% CI: 0.76-1.53; or ovarian cancer, IRR = 1.15, 95% CI: 0.78-1.70. We found a positive association between cadmium and endometrial cancer for the women with BMI<25 (IRR = 1.50, 95% CI: 0.94-2.39), whereas an inverse association was seen for the women with BMI≥25 (IRR = 0.69, 95% CI: 0.42-1.12); p value for interaction = 0.02. CONCLUSIONS: Our study does not indicate that our estimated dietary cadmium intake is associated with hormone-related cancers in women.

Long-term exposure to ambient air pollution and incidence of cerebrovascular events: results from 11 European cohorts within the ESCAPE project.

BACKGROUND: Few studies have investigated effects of air pollution on the incidence of cerebrovascular events. OBJECTIVES: We assessed the association between long-term exposure to multiple air pollutants and the incidence of stroke in European cohorts. METHODS: Data from 11 cohorts were collected, and occurrence of a first stroke was evaluated. Individual air pollution exposures were predicted from land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE). The exposures were: PM2.5 [particulate matter (PM) ≤ 2.5 µm in diameter], coarse PM (PM between 2.5 and 10 µm), PM10 (PM ≤ 10 µm), PM2.5 absorbance, nitrogen oxides, and two traffic indicators. Cohort-specific analyses were conducted using Cox proportional hazards models. Random-effects meta-analysis was used for pooled effect estimation. RESULTS: A total of 99,446 study participants were included, 3,086 of whom developed stroke. A 5-µg/m3 increase in annual PM2.5 exposure was associated with 19% increased risk of incident stroke [hazard ratio (HR) = 1.19, 95% CI: 0.88, 1.62]. Similar findings were obtained for PM10. The results were robust to adjustment for an extensive list of cardiovascular risk factors and noise coexposure. The association with PM2.5 was apparent among those ≥ 60 years of age (HR = 1.40, 95% CI: 1.05, 1.87), among never-smokers (HR = 1.74, 95% CI: 1.06, 2.88), and among participants with PM2.5 exposure < 25 µg/m3 (HR = 1.33, 95% CI: 1.01, 1.77). CONCLUSIONS: We found suggestive evidence of an association between fine particles and incidence of cerebrovascular events in Europe, even at lower concentrations than set by the current air quality limit value.

Performance of multi-city land use regression models for nitrogen dioxide and fine particles.

BACKGROUND: Land use regression (LUR) models have been developed mostly to explain intraurban variations in air pollution based on often small local monitoring campaigns. Transferability of LUR models from city to city has been investigated, but little is known about the performance of models based on large numbers of monitoring sites covering a large area. OBJECTIVES: We aimed to develop European and regional LUR models and to examine their transferability to areas not used for model development. METHODS: We evaluated LUR models for nitrogen dioxide (NO2) and particulate matter (PM; PM2.5, PM2.5 absorbance) by combining standardized measurement data from 17 (PM) and 23 (NO2) ESCAPE (European Study of Cohorts for Air Pollution Effects) study areas across 14 European countries for PM and NO2. Models were evaluated with cross-validation (CV) and hold-out validation (HV). We investigated the transferability of the models by successively excluding each study area from model building. RESULTS: The European model explained 56% of the concentration variability across all sites for NO2, 86% for PM2.5, and 70% for PM2.5 absorbance. The HV R2s were only slightly lower than the model R2 (NO2, 54%; PM2.5, 80%; PM2.5 absorbance, 70%). The European NO2, PM2.5, and PM2.5 absorbance models explained a median of 59%, 48%, and 70% of within-area variability in individual areas. The transferred models predicted a modest-to-large fraction of variability in areas that were excluded from model building (median R2: NO2, 59%; PM2.5, 42%; PM2.5 absorbance, 67%). CONCLUSIONS: Using a large data set from 23 European study areas, we were able to develop LUR models for NO2 and PM metrics that predicted measurements made at independent sites and areas reasonably well. This finding is useful for assessing exposure in health studies conducted in areas where no measurements were conducted.

Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project.

OBJECTIVES: To study the effect of long term exposure to airborne pollutants on the incidence of acute coronary events in 11 cohorts participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). DESIGN: Prospective cohort studies and meta-analysis of the results. SETTING: Cohorts in Finland, Sweden, Denmark, Germany, and Italy. PARTICIPANTS: 100 166 people were enrolled from 1997 to 2007 and followed for an average of 11.5 years. Participants were free from previous coronary events at baseline. MAIN OUTCOME MEASURES: Modelled concentrations of particulate matter <2.5 µm (PM2.5), 2.5-10 µm (PMcoarse), and <10 µm (PM10) in aerodynamic diameter, soot (PM2.5 absorbance), nitrogen oxides, and traffic exposure at the home address based on measurements of air pollution conducted in 2008-12. Cohort specific hazard ratios for incidence of acute coronary events (myocardial infarction and unstable angina) per fixed increments of the pollutants with adjustment for sociodemographic and lifestyle risk factors, and pooled random effects meta-analytic hazard ratios. RESULTS: 5157 participants experienced incident events. A 5 µg/m(3) increase in estimated annual mean PM2.5 was associated with a 13% increased risk of coronary events (hazard ratio 1.13, 95% confidence interval 0.98 to 1.30), and a 10 µg/m(3) increase in estimated annual mean PM10 was associated with a 12% increased risk of coronary events (1.12, 1.01 to 1.25) with no evidence of heterogeneity between cohorts. Positive associations were detected below the current annual European limit value of 25 µg/m(3) for PM2.5 (1.18, 1.01 to 1.39, for 5 µg/m(3) increase in PM2.5) and below 40 µg/m(3) for PM10 (1.12, 1.00 to 1.27, for 10 µg/m(3) increase in PM10). Positive but non-significant associations were found with other pollutants. CONCLUSIONS: Long term exposure to particulate matter is associated with incidence of coronary events, and this association persists at levels of exposure below the current European limit values.