• An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context

      Sullivan, Kristie M.; Enoch, Steven J.; Ezendam, Janine; Sewald, Katherina; Roggen, Erwin L.; Cochrane, Stella; Physicians Committee for Responsible Medicine, Washington, District of Columbia.; School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, England.; National Institute for Public Health and the Environment (RIVM), Centre for Health Protection, Bilthoven, The Netherlands.; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.; et al. (2017-09-07)
    • Afname van foetale en neonatale sterfte in Nederland. Vergelijking met andere EURO-PEROSTAT-Landen in 2004, 2010 en 2015

      Broeders, Lisa; Achterberg, Peter W; Waelput, Adja J M; Ravelli, Anita C J; Kwee, Anneke; Groenendaal, Floris; Offerhaus, Pien; van der Velden, Koos; Rosman, Ageeth N; Nijhuis, Jan G (2019-07-23)
    • Age-Dependent Pre-Vaccination Immunity Affects the Immunogenicity of Varicella Zoster Vaccination in Middle-aged Adults

      van der Heiden, Marieke; de Rond, Lia G. H.; van Zelm, Menno C.; Berbers, Guy A. M.; Boots, Annemieke M. H.; Buisman, Anne-Marie (2018-01-23)
    • Age-related difference in health care use and costs of patients with chronic kidney disease and matched controls: analysis of Dutch health care claims data.

      van Oosten, Manon J M; Logtenberg, Susan J J; Leegte, Martijn J H; Bilo, Henk J G; Mohnen, Sigrid M; Hakkaart-van Roijen, Leona; Hemmelder, Marc H; de Wit, G Ardine; Jager, Kitty J; Stel, Vianda S (2019-10-09)
    • Age-specific Incidence and Prevalence of Keratoconus: A Nationwide Registration Study.

      Godefrooij, Daniel A; de Wit, G Ardine; Uiterwaal, Cuno S; Imhof, Saskia M; Wisse, Robert P L (2017-03)
      To determine the age-specific incidence and prevalence of keratoconus in the modern era of diagnostics.
    • Ageing (- Seveso installations) in the Netherlands.

      Kieskamp, KK; Heezen, PAM; Geus, ECJ (2019-01-28)
    • Aggregate consumer exposure to isothiazolinones via household care and personal care products: Probabilistic modelling and benzisothiazolinone risk assessment.

      Garcia-Hidalgo, Elena; Schneider, Dovilé; von Goetz, Natalie; Delmaar, Christiaan; Siegrist, Michael; Hungerbühler, Konrad (2018-09)
      Consumers regularly use household care and personal care products (HC&PCPs). Isothiazolinones are included in HC&PCPs as preservatives and are being held responsible for an epidemic rise in allergic contact dermatitis (ACD). The objective of this study was to assess the origin and extent of dermal exposure in order to evaluate the risk of ACD from isothiazolinones in HC&PCP. Individual-based aggregate dermal exposure to four isothiazolinones was estimated using the newly proposed Probabilistic Aggregated Consumer Exposure Model-Kinetic, Dermal (PACEM-KD) by combining the reported individual use patterns for HC&PCP in Switzerland (N = 669 (558 adults), ages 0-91) with isothiazolinone concentrations measured in products used by the individual person. PACEM-KD extends the original PACEM by considering exposure duration, product dilution and skin permeability. PACEM-KD-based higher-tier exposure on palms (99th percentile) was 15.4 ng/cm2, 1.3 ng/cm2, 0.9 ng/cm2, and 0.08 ng/cm2 for the isothiazolinones 1,2‑Benzisothiazol‑3‑(2H)‑one (BIT), 2‑Octyl‑3(2H)‑isothiazolinone (OIT), 2‑Methylisothiazolin‑3(2H)‑one (MI), and 5‑Chloro‑2‑methyl‑4‑isothiazolin‑3‑one (CMI), respectively. Major sources of exposure to BIT included all-purpose cleaners, dishwashing detergent, and kitchen cleaner, while exposure to OIT mainly stems from a fungicide. For MI, the main contributors were dishwashing detergent and all-purpose wet wipes, and for CMI all-purpose cleaner. A Quantitative Risk Assessment (QRA) for BIT using Sensitization Assessment Factors (SAFs) indicates that around 1% of the Swiss population is at risk to be sensitized by BIT in cosmetics and household chemicals. For isothiazolinones in general the presented higher-tier modelling approach suggests that household cleaners are currently more important sources of exposure than cosmetics.
    • Aggregation State of Metal-Based Nanomaterials at the Pulmonary Surfactant Film Determines Biophysical Inhibition.

      Yang, Yi; Xu, Lu; Dekkers, Susan; Zhang, Lijie Grace; Cassee, Flemming R; Zuo, Yi Y (2018-08-07)
      Metal-based nanomaterials (MNMs) represent a large category of the engineered nanomaterials, and have been extensively used to enhance the electrical, optical, and magnetic properties of nanoenabled consumer products. Inhaled MNMs can penetrate deeply into the peripheral lung at which they first interact with the pulmonary surfactant (PS) lining of alveoli. Here we studied the biophysical inhibitory potential of representative MNMs on a modified natural PS, Infasurf, using a novel in vitro experimental methodology called the constrained drop surfactometry (CDS). It was found that the biophysical inhibitory potential of six MNMs on Infasurf ranks in the order CeO
    • Aging-related trajectories of lung function in the general population-The Doetinchem Cohort Study.

      van Oostrom, Sandra H; Engelfriet, Peter M; Verschuren, W M Monique; Schipper, Maarten; Wouters, Inge M; Boezen, Marike; Smit, Henriëtte A; Kerstjens, Huib A M; Picavet, H Susan J (2018)
      The objective of this study was to explore trajectories of lung function decline with age in the general population, and to study the effect of sociodemographic and life style related risk factors, in particular smoking and BMI. For this purpose, we used data from the Doetinchem Cohort Study (DCS) of men and women, selected randomly from the general population and aged 20-59 years at inclusion in 1987-1991, and followed until the present. Participants in the DCS are assessed every five years. Spirometry has been performed as part of this assessment from 1994 onwards. Participants were included in this study if spirometric measurement of FEV1, which in this study was the main parameter of interest, was acceptable and reproducible on at least one measurement round, leading to the inclusion of 5727 individuals (3008 females). Statistical analysis revealed three typical trajectories. The majority of participants followed a trajectory that closely adhered to the Global Lung Initiative Reference values (94.9% of men and 96.4% of women). Two other trajectories showed a more pronounced decline. Smoking and the presence of respiratory complaints were the best predictors of a trajectory with stronger decline. A greater BMI over the follow-up period was associated with a more unfavorable FEV1 course both in men (β = -0.027 (SD = 0.002); P < 0.001) and in women (β = -0.008 (SD = 0.001); P < 0.001). Smokers at baseline who quit the habit during follow-up, showed smaller decline in FEV1 in comparison to persistent smokers, independent of BMI change (In men β = -0.074 (SD = 0.020); P < 0.001. In women β = -0.277 (SD = 0.068); P < 0.001). In conclusion, three typical trajectories of age-related FEV1 decline could be distinguished. Change in the lifestyle related risk factors, BMI and smoking, significantly impact aging-related decline of lung function. Identifying deviant trajectories may help in early recognition of those at risk of a diagnosis of lung disease later in life.
    • Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer.

      Walsh, Naomi; Zhang, Han; Hyland, Paula L; Yang, Qi; Mocci, Evelina; Zhang, Mingfeng; Childs, Erica J; Collins, Irene; Wang, Zhaoming; Arslan, Alan A; et al. (2018-12-12)
      Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
    • Air pollution and airway resistance at age 8 years - the PIAMA birth cohort study.

      Finke, Isabelle; de Jongste, Johan C; Smit, Henriette A; Wijga, Alet H; Koppelman, Gerard H; Vonk, Judith; Brunekreef, Bert; Gehring, Ulrike (2018-07-17)
      Air pollution has been found to adversely affect children's lung function. Forced expiratory volume in 1 s and forced vital capacity from spirometry have been studied most frequently, but measurements of airway resistance may provide additional information. We assessed associations of long-term air pollution exposure with airway resistance.
    • Air pollution and incidence of cancers of the stomach and the upper aerodigestive tract in the European Study of Cohorts for Air Pollution Effects (ESCAPE).

      Nagel, Gabriele; Stafoggia, Massimo; Pedersen, Marie; Andersen, Zorana J; Galassi, Claudia; Munkenast, Jule; Jaensch, Andrea; Sommar, Johan; Forsberg, Bertil; Olsson, David; et al. (2018-04-26)
      Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long-term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land-use regression models for particulate matter (PM) below 10 µm (PM10 ), below 2.5 µm (PM2.5 ), between 2.5 and 10 µm (PMcoarse ), PM2.5 absorbance and nitrogen oxides (NO2 and NOX ) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. During average follow-up of 14.1 years of 305 551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 µg/m3 of PM2.5 was 1.38 (95%-CI 0.99;1.92) for gastric and 1.05 (95%-CI 0.62;1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM2.5 was found in men (HR 1.98 (1.30;3.01)) as compared to women (HR 0.85 (0.5;1.45)). This large multicentre cohort study shows an association between long-term exposure to PM2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk. This article is protected by copyright. All rights reserved.
    • Air pollution during New Year's fireworks and daily mortality in the Netherlands.

      Greven, Frans E; Vonk, Judith M; Fischer, Paul; Duijm, Frans; Vink, Nienke M; Brunekreef, Bert (2019-04-05)
      Short-term exposure to air pollution has been associated with cardiovascular and respiratory mortality and morbidity. Little is known about associations between air pollution caused by firework events and daily mortality. We investigated whether particulate matter from fireworks during New Year's celebrations was associated with daily mortality. We analyzed the celebrations of the years 1995-2012. PM
    • Air pollution exposure and lung function until age 16 years: the PIAMA birth cohort study.

      Milanzi, Edith B; Koppelman, Gerard H; Smit, Henriette A; Wijga, Alet H; Oldenwening, Marieke; Vonk, Judith M; Brunekreef, Bert; Gehring, Ulrike (2018-09)
      Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. We investigated associations of air pollution exposure with lung function and lung function growth until age 16.We conducted both longitudinal (n=915) and cross-sectional (n=721) analyses of associations of air pollution exposure with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) growth from ages eight to 16 and FEV1 and FVC at age 16. We estimated residential concentrations of nitrogen dioxide (NO2), "soot" and particulate matter (PMx, where x is the 50% cut-off aerodynamic diameter in µm) with diameters of <2.5 µm (PM2.5), <10 µm (PM10) and 2.5-10 µm (PMcoarse) during the preschool, primary school and secondary school time windows by land use regression models. Associations with (growth in) FEV1 and FVC were analysed by linear (mixed effects) regression.Higher air pollution exposure was associated with reduced FEV1 growth (e.g. adjusted difference -0.26% (95% CI -0.49 to -0.03%) per interquartile range increase in secondary school PM2.5) and lower FEV1 (adjusted difference -2.36% (95% CI -3.76 to -0.94%)), but was not adversely associated with FVC. Associations with FEV1 were stronger in boys than girls and were not modified by asthma status.Higher air pollution exposure may lead to increased airway obstruction, but not reduced lung volume in adolescence.
    • Air Pollution from Livestock Farms Is Associated with Airway Obstruction in Neighboring Residents.

      Borlée, Floor; Yzermans, C Joris; Aalders, Bernadette; Rooijackers, Jos; Krop, Esmeralda; Maassen, Catharina B M; Schellevis, François; Brunekreef, Bert; Heederik, Dick; Smit, Lidwien A M (2017-11-01)
      Livestock farm emissions may not only affect respiratory health of farmers but also of neighboring residents.
    • Airborne emissions from livestock farms and exposure of nearby residents using an atmospheric dispersion model

      Sterk, HAM; Swart, AN; van Leuken, JPG; Schijven, JF; Aarnink, AJA; Wouters, IM; Janse, I; Wichink Kruit, RJ; van Pul, WAJ (2019-01-28)
    • Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.

      Behndig, A F; Mudway, I S; Brown, J L; Stenfors, N; Helleday, R; Duggan, S T; Wilson, S J; Boman, C; Cassee, Flemming R; Frew, A J; et al. (2006-02-01)
      Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.
    • Alcohol consumption and risk of urothelial cell bladder cancer in the European prospective investigation into cancer and nutrition cohort.

      Botteri, E; Ferrari, P; Roswall, N; Tjønneland, A; Hjartåker, A; Huerta, J M; Fortner, R T; Trichopoulou, A; Karakatsani, A; La Vecchia, C; et al. (2017-11-15)
      Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35-70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00-1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01-1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03-2.40) compared to those reporting moderate intakes (<6 g/day), but no dose-response relationship emerged. In men, an increased risk of aggressive forms of UCC was observed even at lower doses (>6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits > 24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01-1.91) and smokers (1.39; 95% CI 1.01-1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking.
    • Alcohol intake in relation to non-fatal and fatal coronary heart disease and stroke: EPIC-CVD case-cohort study.

      Ricci, Cristian; Wood, Angela; Muller, David; Gunter, Marc J; Agudo, Antonio; Boeing, Heiner; van der Schouw, Yvonne T; Warnakula, Samantha; Saieva, Calogero; Spijkerman, Annemieke; et al. (2018-05-29)
      To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke.