Danish Ramazzini Center

BACKGROUND: Prior studies on the association between prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) and child motor development have found contradicting results. Using data collected in the INUENDO cohort in Kharkiv (Ukraine), Warsaw (Poland) and Greenland (N = 1,103) between the years 2002 and 2012, we examined relations of prenatal exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) on motor development and developmental milestones; crawling, standing-up and walking. METHODS: CB-153 and p,p'-DDE were measured in maternal blood in second or third trimester of pregnancy. Motor development was measured in terms of the parentally assessed screening tool Developmental Coordination Disorder Questionnaire 2007 and developmental milestones were assessed via retrospective parental reports of child age at the first time of crawling, standing-up and walking. RESULTS: We saw no associations between tertiles of CB-153 and p,p'-DDE or log-transformed exposures and retrospective reports of the developmental milestones crawling, standing-up and walking in infancy or the motor skills measured as developmental coordination disorder at young school age. CONCLUSIONS: In utero exposure to CB-153 and p,p'-DDE was not associated with parentally retrospectively assessed developmental milestones in infancy or parentally assessed motor skills at young school age. The use of a more sensitive outcome measure may be warranted if subtle effects should be identified.

Background Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE). Methods In this multicentre longitudinal study, we analysed seven population-based cohorts of adults (age ≥30 years) within ELAPSE, from Belgium, Denmark, England, the Netherlands, Norway, Rome (Italy), and Switzerland (enrolled in 2000–11; follow-up until 2011–17). Mortality registries were used to extract the underlying cause of death for deceased individuals. Annual average concentrations of fine particulate matter (PM 2·5 ), nitrogen dioxide (NO 2 ), black carbon, and tropospheric warm-season ozone (O 3 ) from Europe-wide land use regression models at 100 m spatial resolution were assigned to baseline residential addresses. We applied cohort-specific Cox proportional hazard models with adjustment for area-level and individual-level covariates to evaluate associations with non-accidental mortality, as the main outcome, and with cardiovascular, non-malignant respiratory, and lung cancer mortality. Subset analyses of participants living at low pollutant concentrations (as per predefined values) and natural splines were used to investigate the concentration-response function. Cohort-specific effect estimates were pooled in a random-effects meta-analysis. Findings We analysed 28 153 138 participants contributing 257 859 621 person-years of observation, during which 3 593 741 deaths from non-accidental causes occurred. We found significant positive associations between non-accidental mortality and PM 2·5 , NO 2 , and black carbon, with a hazard ratio (HR) of 1·053 (95% CI 1·021–1·085) per 5 μg/m 3 increment in PM 2·5 , 1·044 (1·019–1·069) per 10 μg/m 3 NO 2 , and 1·039 (1·018–1·059) per 0·5 × 10 −5 /m black carbon. Associations with PM 2·5 , NO 2 , and black carbon were slightly weaker for cardiovascular mortality, similar for non-malignant respiratory mortality, and stronger for lung cancer mortality. Warm-season O 3 was negatively associated with both non-accidental and cause-specific mortality. Associations were stronger at low concentrations: HRs for non-accidental mortality at concentrations lower than the WHO 2005 air quality guideline values for PM 2·5 (10 μg/m 3 ) and NO 2 (40 μg/m 3 ) were 1·078 (1·046–1·111) per 5 μg/m 3 PM 2·5 and 1·049 (1·024–1·075) per 10 μg/m 3 NO 2 . Similarly, the association between black carbon and non-accidental mortality was highest at low concentrations, with a HR of 1·061 (1·032–1·092) for exposure lower than 1·5× 10 −5 /m, and 1·081 (0·966–1·210) for exposure lower than 1·0× 10 −5 /m. Interpretation Long-term exposure to concentrations of PM 2·5 and NO 2 lower than current annual limit values was associated with non-accidental, cardiovascular, non-malignant respiratory, and lung cancer mortality in seven large European cohorts. Continuing research on the effects of low concentrations of air pollutants is expected to further inform the process of setting air quality standards in Europe and other global regions. Funding Health Effects Institute.

BACKGROUND: A high body mass index (BMI) has been associated with reduced semen quality and male subfecundity, but no studies following obese men losing weight have yet been published. We examined semen quality and reproductive hormones among morbidly obese men and studied if weight loss improved the reproductive indicators. METHODS: In this pilot cohort study, 43 men with BMI > 33 kg/m² were followed through a 14 week residential weight loss program. The participants provided semen samples and had blood samples drawn, filled in questionnaires, and had clinical examinations before and after the intervention. Conventional semen characteristics as well as sperm DNA integrity, analysed by the sperm chromatin structure assay (SCSA) were obtained. Serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) and inhibin B (Inh-B) were measured. RESULTS: Participants were from 20 to 59 years of age (median = 32) with BMI ranging from 33 to 61 kg/m². At baseline, after adjustment for potential confounders, BMI was inversely associated with sperm concentration (p = 0.02), total sperm count (p = 0.02), sperm morphology (p = 0.04), and motile sperm (p = 0.005) as well as testosterone (p = 0.04) and Inh-B (p = 0.04) and positively associated to estradiol (p < 0.005). The median (range) percentage weight loss after the intervention was 15% (3.5-25.4). Weight loss was associated with an increase in total sperm count (p = 0.02), semen volume (p = 0.04), testosterone (p = 0.02), SHBG (p = 0.03) and AMH (p = 0.02). The group with the largest weight loss had a statistically significant increase in total sperm count [193 millions (95% CI: 45; 341)] and normal sperm morphology [4% (95% CI: 1; 7)]. CONCLUSION: This study found obesity to be associated with poor semen quality and altered reproductive hormonal profile. Weight loss may potentially lead to improvement in semen quality. Whether the improvement is a result of the reduction in body weight per se or improved lifestyles remains unknown.

Abstract Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5 ), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5 , nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 µg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 µg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5 , nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 µg/m 3 an increase of 5 µg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.

Background Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM 2·5 ), nitrogen dioxide (NO 2 ), black carbon, and warm-season ozone (O 3 ) with the incidence of stroke and acute coronary heart disease. Methods We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992–2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011–15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. Findings From the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17·2 years (IQR 13·8–19·5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM 2·5 (hazard ratio 1·10 [95% CI 1·01–1·21] per 5 μg/m 3 increase), NO 2 (1·08 [1·04–1·12] per 10 μg/m 3 increase), and black carbon (1·06 [1·02–1·10] per 0·5 10 −5 /m increase), whereas coronary heart disease incidence was only associated with NO 2 (1·04 [1·01–1·07]). Warm-season O 3 was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM 2·5 and NO 2 remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 μg/m 3 for PM 2·5 and 40 μg/m 3 for NO 2 . Interpretation Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values. Funding Health Effects Institute.

OBJECTIVE: The objective of this review was to evaluate the epidemiologic evidence for a causal relation -between shift work and ischemic heart disease. METHODS: We conducted a systematic search until the end of March 2008 for studies providing information on the relative risk of ischemic heart disease in relation to shift work. The quality of included papers was evaluated with respect to design, exposure and outcome information, bias, and exposure response assessment. RESULTS: Relevant information was retrieved from 14 studies. Seven of these analyzed fatal events, six -combined fatal and non-fatal events, while one study reported separately on both types of events. Relative risks ranged from 0.6-1.4 in 12 papers while two papers reported relative risks around 2.0. Most studies based on fatal events showed no or weak associations while studies that combined fatal and non-fatal events showed modest positive associations. In a majority of studies, we could not reasonably rule out negative or positive bias due to the quality of outcome or exposure information, or confounder control. Five studies used years in shift work for exposure response analysis and no consistent pattern were seen. CONCLUSION: There is limited epidemiological evidence for a causal relation between shift work and ischemic heart disease.

BACKGROUND: Perfluorinated alkyl acids (PFAAs), persistent chemicals with unique water-, dirt-, and oil-repellent properties, are suspected of having endocrine-disrupting activity. The PFAA compounds perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are found globally in humans; because they readily cross the placental barrier, in utero exposure may be a cause for concern. OBJECTIVES: We investigated whether in utero exposure to PFOA and PFOS affects semen quality, testicular volume, and reproductive hormone levels. METHODS: We recruited 169 male offspring (19-21 years of age) from a pregnancy cohort established in Aarhus, Denmark, in 1988-1989, corresponding to 37.6% of the eligible sons. Each man provided a semen sample and a blood sample. Semen samples were analyzed for sperm concentration, total sperm count, motility, and morphology, and blood samples were used to measure reproductive hormones. As a proxy for in utero exposure, PFOA and PFOS were measured in maternal blood samples from pregnancy week 30. RESULTS: Multivariable linear regression analysis suggested that in utero exposure to PFOA was associated with lower adjusted sperm concentration (ptrend = 0.01) and total sperm count (ptrend = 0.001) and with higher adjusted levels of luteinizing hormone (ptrend = 0.03) and follicle-stimulating hormone (ptrend = 0.01). PFOS did not appear to be associated with any of the outcomes assessed, before or after adjustment. CONCLUSIONS: The results suggest that in utero exposure to PFOA may affect adult human male semen quality and reproductive hormone levels.

Abstract Background Some legacy and emerging environmental contaminants are suspected risk factors for intrauterine growth restriction. However, the evidence is equivocal, in part due to difficulties in disentangling the effects of mixtures. Objectives We assessed associations between multiple correlated biomarkers of environmental exposure and birth weight. Methods We evaluated a cohort of 1,250 term (≥ 37 weeks gestation) singleton infants, born to 513 mothers from Greenland, 180 from Poland, and 557 from Ukraine, who were recruited during antenatal care visits in 2002‒2004. Secondary metabolites of diethylhexyl and diisononyl phthalates (DEHP, DiNP), eight perfluoroalkyl acids, and organochlorines (PCB-153 and p,p´-DDE) were quantifiable in 72‒100% of maternal serum samples. We assessed associations between exposures and term birth weight, adjusting for co-exposures and covariates, including prepregnancy body mass index. To identify independent associations, we applied the elastic net penalty to linear regression models. Results Two phthalate metabolites (MEHHP, MOiNP), perfluorooctanoic acid (PFOA), and p,p´-DDE were most consistently predictive of term birth weight based on elastic net penalty regression. In an adjusted, unpenalized regression model of the four exposures, 2-SD increases in natural log–transformed MEHHP, PFOA, and p,p´-DDE were associated with lower birth weight: –87 g (95% CI: –137, –340 per 1.70 ng/mL), –43 g (95% CI: –108, 23 per 1.18 ng/mL), and –135 g (95% CI: –192, –78 per 1.82 ng/g lipid), respectively; and MOiNP was associated with higher birth weight (46 g; 95% CI: –5, 97 per 2.22 ng/mL). Conclusions This study suggests that several of the environmental contaminants, belonging to three chemical classes, may be independently associated with impaired fetal growth. These results warrant follow-up in other cohorts. Citation Lenters V, Portengen L, Rignell-Hydbom A, Jönsson BA, Lindh CH, Piersma AH, Toft G, Bonde JP, Heederik D, Rylander L, Vermeulen R. 2016. Prenatal phthalate, perfluoroalkyl acid, and organochlorine exposures and term birth weight in three birth cohorts: multi-pollutant models based on elastic net regression. Environ Health Perspect 124:365–372; http://dx.doi.org/10.1289/ehp.1408933

BACKGROUND: Animal studies indicate that some phthalate metabolites may harm female reproductive function. OBJECTIVES: We assessed the associations between exposure to phthalate metabolites and pregnancy loss. METHODS: Using a previously established cohort of couples planning their first pregnancy, we analyzed four primary and two oxidized secondary phthalate metabolites in urine samples collected on day 10 after the first day of the last menstrual period before conception occurred (n = 128) and during the previous cycle (if any, n = 111). Subclinical embryonal loss was identified by repeated measurement of urinary human chorionic gonadotropin, and information on clinical spontaneous abortions was obtained by telephone interview with the mother. RESULTS: Pregnancy loss (n = 48) was increased among women with urinary concentration of monoethylhexyl phthalate (MEHP) in the upper tertile in the conception sample compared with women in the lowest tertile [adjusted odds ratio (OR) = 2.9; 95% confidence interval (CI): 1.1, 7.6]. The corresponding OR for subclinical embryonal loss (n = 32) was 40.7 (95% CI: 4.5, 369.5). CONCLUSIONS: The phthalate metabolite MEHP was associated with higher occurrence of pregnancy loss. Because this is the first human study to show this association and the sample size is small, the findings need to be corroborated in independent studies.

OBJECTIVES: The aims of the present study were to (i) cross-culturally adapt a Danish consensus version of the 10-item Perceived Stress Scale (PSS-10) and (ii) evaluate its psychometric properties in terms of agreement, reliability, validity, responsiveness, and interpretability among patients with work-related stress complaints. METHODS: A consensus-building process was performed involving the authors of the three previous Danish translations and the consensus version was back-translated into English and pilot-tested. Psychometric properties of the final version were examined in a sample of 64 patients with work-related stress complaints. RESULTS: The face validity, reliability, and internal consistency of the Danish consensus version of the PSS-10 were satisfactory, and convergent construct validity was confirmed. Receiver operating characteristic (ROC) curves of the change scores showed that the ability of the PSS-10 to correctly classify patients as improved or unchanged according to the patients' own judgment was acceptable. The estimates of minimal clinically important change were 11 points and 28% for absolute and relative change scores, respectively. CONCLUSION: The Danish consensus version of the PSS-10 appears to be feasible for use in clinical research settings and has good psychometric properties in terms of agreement, reliability, validity, responsiveness, and interpretability.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are found widespread in the environment and humans. The relation of PFASs to fertility has now been examined in a relatively large number of epidemiologic studies and a synthesis is in order. The aim of this study was to assess the current human epidemiologic evidence on the association between exposure to PFASs and measures of human fertility, with particular emphasis on perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Systematic literature searches were initially conducted in MEDLINE and EMBASE and subsequently in references and citations of included papers. Studies were included if they assessed exposure to PFASs in biological samples in relation to reproductive hormones, semen characteristics, or time to pregnancy (TTP). Study characteristics and results were abstracted to predefined forms, and the studies were assessed for the risk of bias and confounding. Sixteen studies investigated the association between PFAS exposure in men and semen parameters, reproductive hormone levels, or TTP. There was a lack of consistent results among the numerous investigated exposure-outcome combinations. However, subtle associations between higher PFOS and lower testosterone or abnormal semen morphology cannot be excluded. Eleven studies assessed the association between PFAS exposure in women and TTP or reproductive hormones levels. Four of eight studies found prolonged TTP with higher PFOS or PFOA, but only one study found an association when restricting to nulliparous women. In men, there is little evidence of an association between PFAS exposure and semen quality or levels of reproductive hormones. For PFOS and PFOA, the literature indicates an association with female fecundability in parous women, which is most likely not causal.

BACKGROUND: Perfluorinated compounds (PFCs) have been suspected to adversely affect human reproductive health. The aim of this study was to investigate the associations between PFC exposure and male semen quality. METHODS: PFCs were measured in serum from 588 partners of pregnant women from Greenland, Poland and Ukraine who provided a semen sample, using liquid chromatography tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) could be detected in >97% of the samples. The associations between levels of these compounds and semen volume, sperm concentration, total sperm count, motility and morphology were assessed. RESULTS: Across countries, sperm concentration, total sperm count and semen volume were not consistently associated with PFOS, PFOA, PFHxS or PFNA levels. The proportion of morphologically normal cells was 35% lower [95% confidence interval (CI): 4-66%) for the third tertile of PFOS exposure as compared with the first. A similar reduction was found in relation to increasing PFHxS levels. At the third PFOA exposure tertile, the percentage of motile spermatozoa was 19% (95% CI: 1 to 39%) higher than in the first. CONCLUSIONS: The most robust finding in the present study was the negative associations between PFOS exposure and sperm morphology suggesting adverse effects of PFOS on semen quality, possibly due to interference with the endocrine activity or sperm membrane function. It cannot be excluded that this association and the positive association between PFOA and semen motility, which was not consistent across countries, might represent a chance finding due to the multiple statistical tests being performed.

OBJECTIVE: Missing data is a ubiquitous problem in studies using patient-reported measures, decreasing sample sizes and causing possible bias. In longitudinal studies, special problems relate to attrition and death during follow-up. We describe a methodological approach for the use of multiple imputation (MI) to meet these challenges. METHODS: In a cohort of patients treated with percutaneous coronary intervention followed with use of repetitive questionnaires and information from national registers over 3 years, only 417 out of 1,726 patients had complete data on all measure points and covariates. We suggest strategies for use of MI and different methods for dealing with death along with sensitivity analysis of deviations from the assumption of missing at random, all with the use of standard statistical software. The Mental Component Summary from Short Form 12-item survey was used as an example. CONCLUSION: Ignoring missing data may cause bias of unknown size and direction in longitudinal studies. We have illustrated that MI is a feasible method to try to deal with bias due to missing data in longitudinal studies, including attrition and nonresponse, and should be considered in combination with analysis of sensitivity in longitudinal studies. How to handle dropout due to death is still open for debate.

INTRODUCTION: International research indicates that internal health and safety organizations (HSO) and health and safety committees (HSC) do not have the intended impact on companies' safety performance. The aim of this case study at an industrial plant was to test whether the HSO can improve company safety culture by creating more and better safety-related interactions both within the HSO and between HSO members and the shop-floor. METHODS: A quasi-experimental single case study design based on action research with both quantitative and qualitative measures was used. INTERVENTION: Based on baseline mapping of safety culture and the efficiency of the HSO three developmental processes were started aimed at the HSC, the whole HSO, and the safety representatives, respectively. RESULTS: Results at follow-up indicated a marked improvement in HSO performance, interaction patterns concerning safety, safety culture indicators, and a changed trend in injury rates. These improvements are interpreted as cultural change because an organizational double-loop learning process leading to modification of the basic assumptions could be identified. PRACTICAL APPLICATIONS: The study provides evidence that the HSO can improve company safety culture by focusing on safety-related interactions.

STUDY QUESTION: Does prenatal exposure to perfluoroalkyl substances (PFASs) have long-term effects on female reproductive function?. SUMMARY ANSWER: Our results suggest an association between in utero exposure to perfluorooctanoic acid (PFOA) and delay in age of menarche. WHAT IS KNOWN ALREADY: Previous cross-sectional studies have reported possible effects of PFASs on female reproduction including reduced fecundity, delayed puberty and accelerated age at menopause. Only limited data exist from follow-up studies on long-term implications of prenatal exposure to PFASs. STUDY DESIGN, SIZE, DURATION: In this study we used data from a Danish population-based cohort established in 1988-1989. Of 1212 eligible pregnant women, 965 participated. Follow-up was initiated in 2008 on the female offspring at ∼20 years of age. Three hundred and sixty seven (84%) daughters answered a questionnaire and 267 (61%) daughters furthermore attended clinical examinations which were conducted in 2008-2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: The final study population consisted of 343 daughters of which 254 had attended the clinical examinations and 89 had answered the questionnaire only. Levels of PFASs in maternal serum from pregnancy week 30 were used as a measure of prenatal exposure and related to age of menarche, menstrual cycle length, levels of reproductive hormones and follicle number of the daughters. Data were divided into three groups according to tertiles of maternal concentrations of PFASs (low, medium, high). MAIN RESULTS AND THE ROLE OF CHANCE: In adjusted regression analyses, daughters exposed to higher levels of PFOA in utero had a 5.3 (95% confidence interval: 1.3; 9.3) months later age of menarche compared with the reference group of lower PFOA. Crude (P = 0.05) and adjusted (P = 0.01) trend tests also indicated a relationship between higher prenatal PFOA exposure and delay of menarche. LIMITATIONS, REASONS FOR CAUTION: We did not measure the exact amount of PFASs to which the daughters had been exposed prenatally. Instead we used PFAS concentrations in maternal serum as surrogates. However, PFASs are efficiently transferred to the fetus via placenta. Information on age of menarche was collected retrospectively but the time interval for recall in our study was relatively short (2-10 years). The remaining outcome measures depended on participation in clinical examination which reduced the number of observations leading to limited statistical power and risk of selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Since PFASs can be detected in humans all over the world, effects of prenatal exposure on female reproductive function later in life may have wide health implications. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Danish Council for Independent Research (271-05-0296, 09-065631), the Danish Ministry of Interior and Health (0-302-02-18/5), the Danish Council for Strategic Research (09-067124 (Centre for Fetal Programming), 09-063072, 2101-06-0005), the Novo Nordisk Foundation, the Aarhus University Research Foundation, the Frimodt-Heineke Foundation, the Foundation of Maria Dorthea and Holger From, the Beckett-Foundation, the Research Grant of Organon and the Foundation of Lily Benthine Lund. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence. The “Effects of Low-level Air Pollution: a Study in Europe” (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO2), fine particulate matter (PM2.5), black carbon (BC), and ozone (O3) to assign exposure to cohort participants’ residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines. The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO2, PM2.5, BC and O3 (warm season) were 24.2 µg/m3 (19.5, 29.7), 15.4 µg/m3 (12.8, 17.3), 1.6 10−5m−1 (1.3, 1.8), and 86.6 µg/m3 (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM2.5 (HR: 1.13, 95% CI: 1.05, 1.23 per 5 µg/m3). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 µg/m3. We did not observe associations between NO2, BC or O3 and lung cancer incidence. Long-term ambient PM2.5 exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines.

OBJECTIVE: Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures. METHODS: We used PubMed and Embase to identify relevant original epidemiological peer-reviewed articles, supplemented with citations identified from references in key review articles. This yielded 4528 citations. Articles were excluded for lack of lung function measurement, insufficient occupational exposure classification, lack of either external or internal referents, non-accounting of age or smoking effect, or major analytic inadequacies preventing interpretation of findings. A structured data extraction sheet was used for the remaining 147 articles. Final inclusion was based on a positive qualitative Scottish Intercollegiate Guidelines Network (SIGN) score (≥2+) for study quality, yielding 25 population-wide and 34 industry/occupation-specific studies, 15 on inorganic and 19 on organic dust exposure, respectively. RESULTS: There was a consistent and predominantly significant association between occupational exposures and COPD in 22 of 25 population-based studies, 12 of 15 studies with an inorganic/mineral dust exposure, and 17 of 19 studies on organic exposure, even though the studies varied in design, populations, and the use of measures of exposure and outcome. A nearly uniform pattern of a dose-response relationship between various exposures and COPD was found, adding to the evidence that occupational exposures from vapors, gas, dust, and fumes are risk factors for COPD. CONCLUSION: There is strong and consistent evidence to support a causal association between multiple categories of occupational exposure and COPD, both within and across industry groups.

BACKGROUND: Emerging evidence suggests that prenatal or early-life exposures to environmental contaminants may contribute to an increased risk of asthma and allergies in children. We aimed to the explore associations of prenatal exposures to a large set of environmental chemical contaminants with asthma and eczema in school-age children. METHODS: We studied 1024 mother-child pairs from Greenland and Ukraine from the INUENDO birth cohort. Data were collected by means of an interview-based questionnaire when the children were 5-9 years of age. Questions from the ISAAC study were used to define asthma, eczema, and wheeze. We applied principal components analysis (PCA) to sixteen contaminants in maternal serum sampled during pregnancy, including perfluoroalkyl substances (PFASs), metabolites of diethylhexyl (DEHP) and diisononyl (DiNP) phthalates, PCB-153, and p,p'-DDE. Scores of five principal components (PCs) explaining 70% of the variance were included in multiple logistic regression models. RESULTS: In a meta-analysis that included both populations, the PC2 score, reflecting exposure to DiNP, was negatively associated with current eczema (OR 0.71, 95% CI 0.52-0.96). Other associations were not consistent between the two populations. In Ukrainian children, the PC3 score (DEHP) was positively associated with current wheeze (adjusted OR 1.56, 95% CI 1.03-2.37), whereas the PC5 score, dominated by perfluorooctanoic acid (PFOA), was inversely associated with current wheeze (OR 0.64, 0.41-0.99). In Greenlandic children, a negative association of PC4 (organochlorines) with ever eczema (OR 0.78, 0.61-0.99) was found. CONCLUSIONS: We found limited evidence to support a link between prenatal exposure to environmental chemical contaminants and childhood asthma and eczema.

BACKGROUND: A growing number of studies suggest that maternal stress during pregnancy promotes atopic disorders in the offspring. This is the first systematic review to address prenatal maternal stress (PNMS) and the subsequent risk of atopy-related outcomes in the child. METHODS: The review was performed in accordance to the PRISMA criteria. We searched and selected studies in PubMed, Scopus, Embase and PsychINFO until November 2014. RESULTS: Sixteen (with 25 analyses) of 426 identified articles met the review criteria. Five main PNMS exposures (negative life events, anxiety/depression, bereavement, distress and job strain) and five main atopic outcomes (asthma, wheeze, atopic dermatitis, allergic rhinitis and IgE) were assessed across the studies. Overall, 21 of the 25 analyses suggested a positive association between PNMS and atopic outcomes. Of the 11 exposure-response analyses reported, six found statistically significant trends. CONCLUSION: This systematic review suggests a relationship between maternal stress during pregnancy and atopic disorders in the child. However, the existing studies are of diverse quality. The wide definitions of often self-reported stress exposures imply a substantial risk for information bias and false-positive results. Research comparing objective and subjective measures of PNMS exposure as well as objective measures for atopic outcome is needed.

It is unknown whether the relation between job strain and depression reflects causal characteristics of the working environment or reporting bias. The authors investigated reporting bias by analyzing individual versus work-unit measures of job strain and the risk of depressive symptoms (n = 287) and a diagnosis of depression (n = 97) among 4,291 employees within 378 work units in Aarhus, Denmark, 2007. All participants reported psychological demands and decision latitude, and the authors estimated mean values for each work unit. The odds ratios predicting depressive symptoms or a diagnosis of depression for the highest versus the lowest levels of individual, self-reported high psychological demands and low decision latitude were significantly increased above 2.5. When participants were classified by the work-unit mean levels, these associations were substantially smaller. For depressive symptoms, the odds ratios were 1.49 (95% confidence interval (CI): 0.88, 2.53) and 1.08 (95% CI: 0.84, 1.39), respectively, for psychological demands and decision latitude. For a diagnosis of depression, the odds ratios were 1.33 (95% CI: 0.57, 3.09) and 1.02 (95% CI: 0.68, 1.56), respectively, for psychological demands and decision latitude. These findings indicate that reporting bias inflates associations between job strain and the occurrence of depression, if studies rely on individual self-reports.