Search

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety. Open Access funding enabled and organized by Projekt DEAL. The European Partnership for the Assessment of Risks from Chemicals has received funding from the European Union’s Horizon Europe research and innovation programme under Grant Agreement No 101057014. Co-funding for the UK contribution via Innovate UK project ID 1752317 as part of the Horizon Europe Guarantee fund. Views and opinions expressed are, however, those of the author(s) only and do not necessarily refect those of the European Union or the Health and Digital Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. Sí

In the present review, we synthesize information on the mechanisms of chronic copper (Cu) toxicity using an adverse outcome pathway framework and identify three primary pathways for chronic Cu toxicity: disruption of sodium homeostasis, effects on bioenergetics, and oxidative stress. Unlike acute Cu toxicity, disruption of sodium homeostasis is not a driving mechanism of chronic toxicity, but compensatory responses in this pathway contribute to effects on organism bioenergetics. Effects on bioenergetics clearly contribute to chronic Cu toxicity with impacts at multiple lower levels of biological organization. However, quantitatively translating these impacts into effects on apical endpoints such as growth, amphibian metamorphosis, and reproduction remains elusive and requires further study. Copper-induced oxidative stress occurs in most tissues of aquatic vertebrates and is clearly a significant driver of chronic Cu toxicity. Although antioxidant responses and capacities differ among tissues, there is no clear indication that specific tissues are more sensitive than others to oxidative stress. Oxidative stress leads to increased apoptosis and cellular damage in multiple tissues, including some that contribute to bioenergetic effects. This also includes oxidative damage to tissues involved in neuroendocrine axes and this damage likely alters the normal function of these tissues. Importantly, Cu-induced changes in hormone concentrations and gene expression in endocrine-mediated pathways such as reproductive steroidogenesis and amphibian metamorphosis are likely the result of oxidative stress-induced tissue damage and not endocrine disruption. Overall, we conclude that oxidative stress is likely the primary driver of chronic Cu toxicity in aquatic vertebrates, with bioenergetic effects and compensatory response to disruption of sodium homeostasis contributing to some degree to observed effects on apical endpoints. Environ Toxicol Chem 2022;00:1-18. (c) 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

The primary objective of the present study was to examine the influence of early systemic toxicity resulting from copper (Cu) exposure on metamorphic processes in Xenopus laevis. A 28-day exposure study with copper, initiated at developmental stage 10, was performed using test concentrations of 3.0, 9.0, 27.2, 82.5, and 250 μg Cu/L. The primary endpoints included mortality, developmental stage, embryo-larval malformation, behavioral effects, hindlimb length (HLL), growth (snout-vent length [SVL] and wet body weight), and histopathology. The 28-day LC50 value with 95% confidence intervals was 61.2 (51.4-72.9) μg Cu/L with 250 μg Cu/L resulting in complete lethality. Developmental arrest in the 82.5 and delay in the 27.2 μg Cu/L treatments was observed as early as study day 10 continuing throughout the remainder of exposure. SVL-normalized HLL, body weight, and SVL in the 27.2 and 82.5 μg Cu/L treatments were significantly decreased relative to control. At 82.5 μg Cu/L, and thyroid gland size was markedly reduced when compared with controls consistent with the stage of developmental and growth arrest. Concentration-dependent findings in the intestine, liver, gills, eyes, and pharyngeal mucosa were consistent with non-endocrine systemic toxicity. These were prevalent in the 9.0 and 27.2 μg Cu/L treatment groups but were minimally evident or absent in the 82.5 μg/L group, which was attributed to developmental arrest. In conclusion, developmental delay in larvae exposed to 27.2 and 82.5 μg Cu/L was the result of systemic toxicity occurring in early development prior hypothalomo-pituitary-thyroid axis (HPT)-driven metamorphosis and was not indicative of endocrine disruption.

The eIF4E family of translation initiation factors bind 5’ methylated caps and act as the limiting-step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Funding Information: This work was supported by the European Union's Horizon 2020 research and innovation program projects HBM4EU [grant number 733032 ]. Authors acknowledge the editorial assistance of Richard Davies. Publisher Copyright: © 2023 The Author(s) Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of validated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxicological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′-deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU confirms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better understand the public health implications of human exposure to environmental chemicals. publishersversion published

Current approaches for the assessment of environmental and human health risks due to exposure to chemical substances have served their purpose reasonably well. Nevertheless, the systems in place for different uses of chemicals are faced with various challenges, ranging from a growing number of chemicals to changes in the types of chemicals and materials produced. This has triggered global awareness of the need for a paradigm shift, which in turn has led to the publication of new concepts for chemical risk assessment and explorations of how to translate these concepts into pragmatic approaches. As a result, next-generation risk assessment (NGRA) is generally seen as the way forward. However, incorporating new scientific insights and innovative approaches into hazard and exposure assessments in such a way that regulatory needs are adequately met has appeared to be challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) has been designed to address various challenges associated with innovating chemical risk assessment. Its overall goal is to consolidate and strengthen the European research and innovation capacity for chemical risk assessment to protect human health and the environment. With around 200 participating organisations from all over Europe, including three European agencies, and a total budget of over 400 million euro, PARC is one of the largest projects of its kind. It has a duration of seven years and is coordinated by ANSES, the French Agency for Food, Environmental and Occupational Health & Safety.

Background: Kisspeptin has been proposed as an effect biomarker to understand the mechanisms by which some environmental chemicals adversely affect the human reproductive system. Objective: To ascertain whether kisspeptin serum protein and DNA methylation levels are associated with exposure to several environmental chemicals (individually and as a mixture) and serum reproductive hormone levels in adolescent males. Methods: Three phenols (bisphenol A [BPA], methyl-paraben [MPB], and benzophenone-3 [BP3]); two toxic metals (arsenic and cadmium); and four metabolites of non-persistent pesticides, including insecticides (2-isopropyl-6- methyl-4-pyrimidinol [IMPy], malathion diacid [MDA], and dimethylcyclopropane carboxylic acid [DCCA]) and fungicides (ethylene thiourea [ETU]) were measured in first-morning urine samples of 133 adolescent males aged 15–17 years from the INMA-Granada cohort. In blood samples collected on the same day, KISS1 gene DNA methylation was measured at four CpGs from the Exon IV, as well as serumlevels of kiss54 protein, total testosterone (T), estradiol (E2), sex hormone binding-globulin, dehydroepiandrosterone sulfate, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Multiple linear regression and mixture (quantile g-computation) models were fit. Results: UrinaryMDA and DCCA concentrations were associatedwith higher kiss54 levels [%change (95%CI) for each log-unit increase in concentration = 2.90 (0.32;5.56), and 1.93 (0.45,3.43), respectively]; IMPy with lower DNA methylation percentage at CpG1 and total CpGs [% change (95%CI) = −1.15 (−1.96;-0.33): −0.89 (−1.73;- 0.01), respectively]; and BP3 and DCCA with lower total CpGs methylation [−0.53 (−1.04;-0.01) and − 0.69 (−1.37;-0.01), respectively]. The pesticide mixture and the whole chemical mixture were associated with higher kiss54 [% change (95%CI) = 9.09 (3.29;15.21) and 11.61 (3.96;19.82), respectively] and lower methylation levels at several CpGs. Additionally, serum kiss54 in the third tertile was associated with higher LH levels [% change (95%CI) = 28.69 (3.75–59.63)], and third-tertile CpG1, CpG2, and total CpG methylation percentages were associated with lower FSH and E2. Conclusion: The findings of the present study and the negative correlation between serumkiss54 levels and KISS1 DNA methylation percentages suggested that kisspeptin may be a promising effect biomarker., European Union's Horizon 2020 research and innovation program 733032 CP16/00085, Instituto de Salud Carlos III PI 17/01526 PT17/0019, Human Genotyping Laboratory at the Spanish National Cancer Research Centre UCE-PP2017-06, Instituto de Salud Carlos III European Commission European Commission, Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP), University of Granada CPII21/00014, Ramon Areces Foundation, Miguel Servet Type II program of the ISCIII, European Commission, Spanish Government

The European Joint Programme HBM4EU coordinated and advanced human biomonitoring (HBM) in Europe in order to provide science-based evidence for chemical policy development and improve chemical management. Arsenic (As) was selected as a priority substance under the HBM4EU initiative for which open, policy relevant questions like the status of exposure had to be answered. Internal exposure to inorganic arsenic (iAs), measured as Toxic Relevant Arsenic (TRA) (the sum of As(III), As(V), MMA, DMA) in urine samples of teenagers differed among the sampling sites (BEA (Spain) > Riksmaten adolescents (Sweden), ESTEBAN (France) > FLEHS IV (Belgium), SLO CRP (Slovenia)) with geometric means between 3.84 and 8.47 μg/L. The ratio TRA to TRA + arsenobetaine or the ratio TRA to total arsenic varied between 0.22 and 0.49. Main exposure determinants for TRA were the consumption of rice and seafood. When all studies were combined, Pearson correlation analysis showed significant associations between all considered As species. Higher concentrations of DMA, quantitatively a major constituent of TRA, were found with increasing arsenobetaine concentrations, a marker for organic As intake, e.g. through seafood, indicating that other sources of DMA than metabolism of inorganic As exist, e.g. direct intake of DMA or via the intake of arsenosugars or -lipids. Given the lower toxicity of DMA(V) versus iAs, estimating the amount of DMA not originating from iAs, or normalizing TRA for arsenobetaine intake could be useful for estimating iAs exposure and risk. Comparing urinary TRA concentrations with formerly derived biomonitoring equivalent (BE) for non-carcinogenic effects (6.4 μg/L) clearly shows that all 95th percentile exposure values in the different studies exceeded this BE. This together with the fact that cancer risk may not be excluded even at lower iAs levels, suggests a possible health concern for the general population of Europe. HBM4EU is co-financed under Horizon 2020 (grant agreement No 733032). The authors thank all investigators of the contributing studies for their participation and contribution to the joint HBM4EU survey and the national programme owners for their financial support. Also thanks to the participating teenagers and their families, the field workers that collected the samples. The FLEHS IV study was conducted within the framework of the Flemish Center of Expertise on Environment and Health (FLEHS 2016–2020) and funded by the Flemish Government, Department of Environment & Spatial Development. We thank the teenagers and their families that participated in the study, the field workers from the Pro vincial Institute of Hygiene and VITO for the sample and data collection. All collaborators of the scientific teams of the Flemish Center of Expertise on Environment and Health (https://www.milieu-en-gezondheid.be/en/about-the-center-0) and Karen Van Campenhout and Caroline Teughels from the Flemish Department of Environment & Spatial Development for their valuable input in the field work committee. The funding of the German Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection is gratefully acknowledged. BEA study was co-funded by the Spanish Ministry of Agriculture, Fisheries and Food and the Insituto de Salud Carlos III (SEG 1321/15). In Slovenia the work was cofounded by the Slovenian Research Funding Agency – ARRS through a research programme P-0143. ESTEBAN was Funded by Sant´e Publique France and the French ministries of Health and the Environment. The study of RIKSMATEN was conducted and mainly financed by the Swedish Food Agency. Financial support was provided from the Swedish Civil Contingencies Agency and from the Swedish Environmental Pro tection Agency (SEPA). Sí

Human biomonitoring (HBM) studies have highlighted widespread daily exposure to environmental chemicals. Some of these are suspected to contribute to adverse health outcomes such as reproductive, neurological, and metabolic disorders, among other developmental and chronic impairments. One of the objectives of the H2020 European Human Biomonitoring Initiative (HBM4EU) was the development of informative effect biomarkers for application in a more systematic and harmonized way in large-scale European HBM studies. The inclusion of effect biomarkers would complement exposure data with mechanistically-based information on early and late adverse effects. For this purpose, a stepwise strategy was developed to identify and implement a panel of vali- dated effect biomarkers in European HBM studies. This work offers an overview of the complete procedure followed, from comprehensive literature search strategies, selection of criteria for effect biomarkers and their classification and prioritization, based on toxi- cological data and adverse outcomes, to pilot studies for their analytical, physiological, and epidemiological validation. We present the example of one study that demonstrated the mediating role of the effect biomarker status of brain-derived neurotrophic factor BDNF in the longitudinal association between infant bisphenol A (BPA) exposure and behavioral function in adolescence. A panel of effect biomarkers has been implemented in the HBM4EU Aligned Studies as main outcomes, including traditional oxidative stress, reproductive, and thyroid hormone biomarkers. Novel biomarkers of effect, such as DNA methylation status of BDNF and kisspeptin (KISS) genes were also evaluated as molecular markers of neurological and reproductive health, respectively. A panel of effect biomarkers has also been applied in HBM4EU occupational studies, such as micronucleus analysis in lymphocytes and reticulocytes, whole blood comet assay, and malondialdehyde, 8-oxo-2′ -deoxyguanosine and untargeted metabolomic profile in urine, to investigate, for example, biological changes in response to hexavalent chromium Cr(VI) exposure. The use of effect biomarkers in HBM4EU has demonstrated their ability to detect early biological effects of chemical exposure and to identify subgroups that are at higher risk. The roadmap developed in HBM4EU con- firms the utility of effect biomarkers, and support one of the main objectives of HBM research, which is to link exposure biomarkers to mechanistically validated effect and susceptibility biomarkers in order to better un- derstand the public health implications of human exposure to environmental chemicals., European Union’s Horizon 2020 research and innovation program projects HBM4EU 733032

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA., European Commission 733032 857560 101057014, Ministry of Education, Youth and Sports by the RECETOX Research Infrastructure LM2018121, OP RDE project CETOCOEN Excellence CZ.02.1.01/0.0/0.0/17_043/0009632, Japan Agency for Medical Research and Development (AMED) JP21mk0101216 JP22mk0101216, Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT), Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (KAKENHI) 21K12133

Objectives The debilitating nature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) means that family members often take on a caring role. This study compared the experiences of people caring for three groups: youth, young adults, spouses. Methods An opportunistic sample of 36 carers completed an online survey of open-ended questions asking about their experiences. Thematic analysis was used to consider the three sets of responses separately and Thematic Comparison was used to identify points of connection and disconnection across the sets. Results The themes identified were very similar to those identified in past studies. Two super-ordinate themes were identified: “Lack of knowledge and understanding” and “Holistic Impact”. Though most sub-ordinate themes were evident across all three groups, important differences were found. The sub-ordinate themes “Caring Blindly”, “Emotional and physical health cost”, and “Impact on the whole family” were more evident amongst carers of youth while the theme “Worry for the future” was more evident from carers of young adults and spouses. Discussion Differences seemed to be related to both the time since diagnosis and the life stage. A longitudinal study would help to understand how carer experiences change over the life course of caring for someone with ME/CFS.

Acute Myeloid Leukemia (AML) is a heterogeneous malignancy involving the clonal expansion of myeloid stem and progenitor cells in the bone marrow and peripheral blood. Most AML patients eligible for potentially curative treatment receive intensive chemotherapy. Risk stratification is used to optimize treatment intensity and transplant strategy, and is mainly based on cytogenetic screening for structural chromosomal alterations and targeted sequencing of a selection of common mutations. However, the forecasting accuracy of treatment response remains modest. Recently,ex vivodrug screening has gained traction for its potential in personalized treatment selection, as well as a tool for identifying and mapping patient groups based on relevant cancer dependencies. We systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show thatex vivodrug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion,ex vivodrug profiling can accurately assess risk of individual AML patients and may guide clinical decision-making.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL (R) DINCH) on children's neurodevelopment is limited. The aim of the present research is to evaluate the association between phthalate /HEXAMOLL (R) DINCH exposure and child neurodevelopment in three European cohorts involved in HBM4EU Aligned Studies. Participating subjects were school-aged children belonging to the Northern Adriatic cohort II (NAC-II), Italy, Odense Child Cohort (OCC), Denmark, and PCB cohort, Slovakia. In each cohort, children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score (FSIQ) of the Wechsler Intelligence Scale of Children test using three different editions. The children's urine samples, collected for one point in time concurrently with the neurodevelopmental evaluation, were analyzed for several phthalates/HEXAMOLL (R) DINCH biomarkers. The relation between phthalates/HEXAMOLL (R) DINCH and FSIQ was explored by applying separate multiple linear regressions in each cohort. The means and standard deviations of FSIQ were 109 +/- 11 (NAC-II), 98 +/- 12 (OCC), and 81 +/- 15 (PCB cohort). In NAC-II, direct associations between FSIQ and DEHP's biomarkers were found: 50H-MEHP+5oxo-MEHP ((3 = 2.56; 95% CI 0.58-4.55; N = 270), 50H-MEHP+5cx-MEPP (beta = 2.48; 95% CI 0.47-4.49; N = 270) and 5OH-MEHP (beta = 2.58; 95% CI 0.65-4.51; N = 270). On the contrary, in the OCC the relation between DEHP's biomarkers and FSIQ tended to be inverse but imprecise (p-value >= 0.10). No associations were found in the PCB cohort. FSIQ was not associated with HEXAMOLL (R) DINCH in any cohort. In conclusion, these results do not provide evidence of an association between concurrent phthalate/DINCHHEXAMOLLR DINCH exposure and IQ in children., European Commission 733032 European Union through its Sixth Framework Program for RTD FOOD-CT-2006-016253, Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy (Ministry of Health-Italy) RC 12/12, CROME LIFE Project "Cross-Mediterranean Environment and Health Network" LIFE12 ENV/GR/001040, Odense University Hospital, Denmark, University of Southern Denmark Mental Health Service of the Region of Southern Denmark Odense Patient data Exploratory Network (OPEN), Denmark Danish Center for Hormone Disrupting Chemicals MST-611-00012, Det Frie Forskningsrad (DFF) 4004-00352B_FSS, Novo Nordisk Foundation NNF19OC0058266 NNF17OC0029404, Sygeforsikring Danmark 2021-0173, Odense University Hospital, Helsefonden Beckettfonden, Danish Mental Health Fund, Health Insurance Denmark, Velux Fonden, Slovak Research and Development Agency APVV-0571-12, Ministry of Health of the Slovak Republic 2014/47-SZU-11, Region of Southern Denmark, The Municipality of Odense, Denmark, Rigshospitalet

The interaction between morphology, performance, and ecology has long been studied in order to explain variation in the natural world. Within arboreal salamanders, diversification in foot morphology and microhabitat use are thought to be linked by the impact of foot size and shape on clinging and climbing performance, resulting in an ability to access new habitats. We examine whether various foot shape metrics correlate with stationary cling performance and microhabitat to explicitly quantify this performance gradient across 14 species of salamander, including both arboreal and nonarboreal species. Clinging performance did not correlate with foot shape, as quantified by landmark‐based geometric morphometrics, nor with microhabitat use. Mass‐corrected foot centroid size and foot contact area, on the other hand, correlated positively with clinging performance on a smooth substrate. Interestingly, these foot variables correlated negatively with clinging performance on rough substrates, suggesting the use of multiple clinging mechanisms dependent upon the texture of the surface. These findings demonstrate that centroid size and foot contact area are more functionally relevant for clinging in salamanders than foot shape, suggesting that foot shape need not converge in order to achieve convergent performance. More broadly, our results provide an example of how the quantification of the performance gradient can provide the appropriate lens through which to understand the macroevolution of morphology and ecology., Arboreal salamanders have confounded herpetologists for years. We test the relationship between form and function of foot shape with respect to arboreality, showing no dependence of clinging performance on foot shape or microhabitat use. Rather, mass‐corrected foot centroid size and foot contact area do confer differences in cling performance.

Chemical contamination from point source discharges in developed (resource-rich) countries has been widely regulated and studied for decades; however, diffuse sources are largely unregulated and widespread. In the European Union (EU), large dischargers report releases of some chemicals, yet little is known of total emissions (point and diffuse) and their relative significance. We estimated copper loadings from all significant sources including industry, sewage treatment plants, surface runoff (from traffic, architecture, and atmospheric deposition), septic tanks, agriculture, mariculture, marine transport (antifoulant leaching), and natural processes. A combination of European datasets, literature, and industry data were used to generate export coefficients. These were then multiplied by activity rates to derive loads. A total of approximately 8 kt of copper per annum (ktpa) is estimated to enter freshwaters in the EU, and another 3.5 ktpa enters transitional and coastal waters. The main inputs to freshwater are natural processes (3.7 ktpa), agriculture (1.8 ktpa), and runoff (1.8 ktpa). Agricultural emissions are dominated by copper-based plant protection products and farmyard manure. Urban runoff is influenced by copper use in architecture and by vehicle brake linings. Antifoulant leaching from boats (3.2 ktpa) dominates saline water loads of copper. It is noteworthy that most of the emissions originate in a limited number of copper uses where environmental exposure and pathways exist, compared with the bulk of copper use within electrical and electronic equipment and infrastructure that has no environmental pathway during its use. A sensitivity analysis indicated significant uncertainty in data from abandoned mines and urban runoff load estimates. This study provided for the first time a methodology and comprehensive metal load apportionment to European aquatic systems, identifying data gaps and uncertainties, which may be refined over time. Source apportionments using this methodology can inform more cost-effective environmental risk assessment and management. Integr Environ Assess Manag 2022;00:1-17. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental ToxicologyChemistry (SETAC).

The eIF4E family of translation initiation factors bind 5’ methylated caps and act as the limiting-step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting Eif4e1c functions in a novel pathway. Deletion ofeif4e1cin zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Althougheif4e1cis broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Information about the effects of phthalates and non-phthalate substitute cyclohexane-1,2-dicarboxylic acid diisononyl ester (HEXAMOLL

Background: Although drinking water in the Netherlands is generally accepted as safe, public concern about health risks of long-term intake still exist.Objective: The aim was to explore associations between drinking water quality for nitrate, water hardness, calcium and magnesium and causes-of-death as related to cardiovascular diseases amongst which coronary heart disease and colorectal cancer.Methods: We used national administrative databases on cause-specific mortality, personal characteristics, residential history, social economic indicators, air quality and drinking water quality for parameters specified by the EU Drinking Water Directive. We put together a cohort of 6,998,623 persons who were at least 30 years old on January 1, 2008 and lived for at least five years on the same address. The average drinking water concentration over 2000–2010 at the production stations were used as exposure indicators. We applied age stratified Cox proportional hazards models. Results: Magnesium was associated with a reduced risk for mortality due to coronary heart diseases: HR of 0.95 (95% CI: 0.90, 0.99) per 10 mg/L increase. For mortality due to cardiovascular diseases, a 100 mg/L increase in calcium was associated with a HR of 1.08 (95% CI: 1.03, 1.13) and an increase of 2.5 mmol/L of water hardness with a HR of 1.06 (95% CI: 1.01, 1.10). The results show an elevated risk for coronary heart disease mortality at calcium concentrations below 30 mg/L, but over the whole exposure range no exposure response relation was observed. For other combinations of drinking water quality parameters and cause-specific mortality studied, no statistical significant associations were identified.Conclusion: We identified in this explorative study a protective effect of magnesium for the risk of mortality to coronary heart disease. Also we found an increased risk of mortality due to cardiovascular disease associated with the concentration of calcium and the water hardness in drinking water.

Highly polar chemicals are mobile in an aqueous environment. Analytical methods for these compounds in water are lacking. A combined target/nontarget screening method based on hydrophilic interaction LC coupled to high-resolution MS was developed. Thirty-two highly polar chemicals (including melem and melam) can thus be quantitatively measured in surface water and drinking water, and the MS data can be screened for unknown compounds. This is the first time a method for the determination of melem and melam in water has been described. The method is complementary to existing target and nontarget methods for less polar substances and can be applied for (drinking) water quality assessment. In a screening study in The Netherlands and Flanders, 12 of the 32 compounds were encountered in groundwater, surface water, and drinking water at levels between 0.01 and 4.2 μg/L. Concentrations in drinking water were compared with (provisional) guideline values to assess whether these may pose a concern for human health. In one drinking water sample, the concentration of dichloroacetic acid exceeded the provisional guideline value, indicating that health effects cannot be excluded on the basis of lifetime exposure. For most chemicals, reliable drinking water guideline values could not be derived due to the limited available of toxicity data.

The importance of considering the bioavailability of metals in understanding and assessing their toxicity in freshwaters has been recognized for many years. Currently, biotic ligand models (BLMs) are being applied for the derivation and implementation of environmental quality standards (EQS) for metals under the Water Framework Directive in Europe. bio-met is a simplified tool that was developed for implementing bioavailability-based EQS for metals in European freshwaters. We demonstrate the reliability of the relationship between the full BLM predictions and the thresholds (hazardous concentration affecting 5% of species [HC5] values) predicted by bio-met in 3 stages, for the metals copper, nickel, and zinc. First, ecotoxicity data for specific species from laboratory tests in natural waters are compared with predictions by the individual species BLMs included in the full BLMs. Second, the site-specific HC5 values predicted by bio-met for the natural waters used for ecotoxicity testing are compared with those provided by the full BLMs. The reliability of both relationships is demonstrated for all 3 metals, with more than 80% of individual species BLM predictions being within a factor of 3 of the experimental results, and 99% of bio-met local HC5 predictions being within a factor of 2 of the full BLM result. Third, using a larger set of European natural waters in addition demonstrates the reliability of bio-met over a broad range of water chemistry conditions. bio-met is therefore an appropriate tool for performing compliance assessments against EQS values in Europe, due to the demonstrated consistency with the toxicity test data. Environ Toxicol Chem 2020;39:2361-2377. © 2020 SETAC.

Complementing biology lecture courses with laboratory sections is nearly universal at undergraduate institutions, yet many topics in biology do not easily lend themselves to experiment-based labora...

Effects-based methods (EBMs) are considered part of a more integrative strategy for regulating substances of concern under the European Union Water Framework Directive. In general, EBMs have been demonstrated as useful indicators of effects on biota, although links to population and community-level effects are sometimes uncertain. When EBMs are sufficiently specific and sensitive, and links between measured endpoints and apical or higher level effects are established, they can be a useful tool in assessing effects from a specific toxicant or class of toxicants. This is particularly valuable for toxicants that are difficult to measure and for assessing the effects of toxicant mixtures. This paper evaluates 12 EBMs that have been proposed for potential use in the assessment of metals. Each EBM was evaluated with respect to metal specificity and sensitivity, sensitivity to other classes of toxicants, and the strength of the relationship between EBM endpoints and effects observed at the whole organism or population levels of biological organization. The evaluation concluded that none of the EBMs evaluated meet all three criteria of being sensitive to metals, insensitive to other classes of toxicants, and a strong indicator of effects at the whole organism or population level. Given the lack of suitable EBMs for metals, we recommended that the continued development of mixture biotic ligand models (mBLMs) may be the most effective way to achieve the goal of a more holistic approach to regulating metals in aquatic ecosystems. Given the need to further develop and validate mBLMs, we suggest an interim weight-of-evidence approach that includes mBLMs, macroinvertebrate community bioassessment, and measurement of metals in key macroinvertebrate species. This approach provides a near-term solution and simultaneously generates data needed for the refinement and validation of mBLMs. Once validated, it should be possible to rely primarily on mBLMs as an alternative to EBMs for metals. Integr Environ Assess Manag 2022;00:1-8. (c) 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Evolutionary biologists have long been interested in the macroevolutionary consequences of various selection pressures, yet physiological responses to selection across deep time are not well understood. In this paper, we investigate how a physiologically relevant morphological trait, surface area to volume ratio (SA:V) of lungless salamanders, has evolved across broad regional and climatic variation. SA:V directly impacts an organisms' ability to retain water, leading to the expectation that smaller SA:Vs would be advantageous in arid, water-limited environments. To explore the macroevolutionary patterns of SA:V, we first develop an accurate method for estimating SA:V from linear measurements. Next, we investigate the macroevolutionary patterns of SA:V across 257 salamander species, revealing that higher SA:Vs phylogenetically correlate with warmer, wetter climates. We also observe higher SA:V disparity and rate of evolution in tropical species, mirrored by higher climatic disparity in available and occupied tropical habitats. Taken together, these results suggest that the tropics have provided a wider range of warmer, wetter climates for salamanders to exploit, thereby relaxing desiccation pressures on SA:V. Overall, this paper provides an accurate, efficient method for quantifying salamander SA:V, allowing us to demonstrate the power of physiological selection pressures in influencing the macroevolution of morphology.

Publicly available chemical assessments of hydraulic fracturing related waters are generally based on shale gas practices in the U.S. There is a lack of information on hydraulic fracturing related gas development from EU countries and more generally on other types of extractions. This research fills this knowledge gap by presenting chemical and bioassay assessments of hydraulic fracturing related waters from a tight gas development in the Netherlands. Fracturing fluid, flowback water and groundwater from surrounding aquifers before and after the actual fracturing were analysed by means of high resolution liquid chromatography tandem mass spectrometry, the Ames test and three chemical activated luciferase gene expression bioassays aimed at determining genotoxicity, oxidative stress response and polyaromatic hydrocarbon contamination.After sample enrichment a higher number of peaks can be found in both fracturing fluid and flowback samples. No clear differences in chemical composition were shown in the groundwater samples before and after hydraulic fracturing. Preliminary environmental fate data of the tentatively identified chemicals points towards persistence in water. Clear genotoxic and oxidative stress responses were found in the fracturing fluid and flowback samples. A preliminary suspect screening resulted in 25 and 36 matches in positive and negative ionisation respectively with the 338 possible suspect candidates on the list.Extensive measures relating to the handling, transport and treatment of hydraulic fracturing related waters are currently in place within the Dutch context. The results of the present study provide a scientific justification for such measures taken to avoid adverse environmental and human health impacts.

An extension of the transformation/dissolution protocol (T/DP) was developed and evaluated as a tool to measure the removal of metals from the water column for chronic aquatic hazard classification. The T/DP extension (T/DP-E) consists of 2 parts: T/DP-E part 1, to measure metal removal from the water column via binding of metals to a substrate and subsequent settling, and T/DP-E part 2, to assess the potential for remobilization of metals following resuspension. The T/DP-E methodology (672-h [28-d] removal period, 1-h resuspension event, and 96-h resettling period) was tested using Cu, Co, and Sr solutions in the presence of a substrate. The metal removal rates varied from rapid removal for Cu to slower rates of removal for Co and Sr. The resuspension event did not trigger any increase in dissolved Cu, Co, or Sr. Additional 96-h experiments were conducted using dissolved Ni, Pb, Zn, and Ag and supported the conclusion that the T/DP-E is sufficiently robust to distinguish removal rates between metals with a wide range of reactivities. The proposed method provides a means to quantify the rate of metal removal from the water column and evaluate remobilization potential in a standardized and reliable way. Environ Toxicol Chem 2019;38:2032-2042. © 2019 SETAC.

Background Adolescents and young adults (AYAs; 16-25 years old) with cancer may be particularly affected by social interactions, as they can be grappling with a serious illness and normal developmental challenges. Objectives The aims of this study were to explore interactions relevant to AYA survivors and cancer and to investigate whether specific interactions are experienced as more and less helpful. Methods Ten semistructured interviews were conducted with AYAs, with questions pertaining to their psychosocial interactions and any developmental effects from having cancer. Five follow-up interviews were conducted approximately 12 months later, a 50% response rate. Results Thematic analysis identified a range of themes including the importance of personal privacy and controlled sharing of information, independence, identity formation, positivity, acknowledgement of cancer versus being treated normally, and receiving support instead of supporting others. In the 1-year follow-up interviews, half of these themes remained constant; however, the personal privacy, independence, and supporting others themes changed. Conclusions Overall, social support, social interactions, and developmental stage seem to influence the overall cancer experience. Development seems to be impacted by cancer for both adolescents and young adults, but this impact lessened over a 1-year period for the 50% of participants who participated in both interviews. Implications for practice It is believed that a more comprehensive understanding of AYA patients' psychosocial experiences related to cancer will enable those who interact with this group to provide more positive support through their interactions with individuals.

The United Nations and the European Union have developed guidelines for the assessment of long-term (chronic) chemical environmental hazards. This approach recognizes that these hazards are often related to spillage of chemicals into freshwater environments. The goal of the present study was to examine the concept of metal ion removal from the water column in the context of hazard assessment and classification. We propose a weight-of-evidence approach that assesses several aspects of metals including the intrinsic properties of metals, the rate at which metals bind to particles in the water column and settle, the transformation of metals to nonavailable and nontoxic forms, and the potential for remobilization of metals from sediment. We developed a test method to quantify metal removal in aqueous systems: the extended transformation/dissolution protocol (T/DP-E). The method is based on that of the Organisation for Economic Co-operation and Development (OECD). The key element of the protocol extension is the addition of substrate particles (as found in nature), allowing the removal processes to occur. The present study focused on extending this test to support the assessment of metal removal from aqueous systems, equivalent to the concept of "degradability" for organic chemicals. Although the technical aspects of our proposed method are different from the OECD method for organics, its use for hazard classification is equivalent. Models were developed providing mechanistic insight into processes occurring during the T/DP-E method. Some metals, such as copper, rapidly decreased (within 96 h) under the 70% threshold criterion, whereas others, such as strontium, did not. A variety of method variables were evaluated and optimized to allow for a reproducible, realistic hazard classification method that mimics reasonable worst-case scenarios. We propose that this method be standardized for OECD hazard classification via round robin (ring) testing to ascertain its intra- and interlaboratory variability. Environ Toxicol Chem 2019;38:1839-1849. © 2019 SETAC.

Evolutionary theory predicts that selection in distinct microhabitats generates correlations between morphological and ecological traits, and may increase both phenotypic and taxonomic diversity. However, some microhabitats exert unique selective pressures that act as a restraining force on macroevolutionary patterns of diversification. In this study, we use phylogenetic comparative methods to investigate the evolutionary outcomes of inhabiting the arboreal microhabitat in salamanders. We find that arboreality has independently evolved at least five times in Caudata and has arisen primarily from terrestrial ancestors. However, the rate of transition from arboreality back to terrestriality is 24 times higher than the converse. This suggests that macroevolutionary trends in microhabitat use tend toward terrestriality over arboreality, which influences the extent to which use of the arboreal microhabitat proliferates. Morphologically, we find no evidence for an arboreal phenotype in overall body proportions or in foot shape, as variation in both traits overlaps broadly with species that utilize different microhabitats. However, both body shape and foot shape display reduced rates of phenotypic evolution in arboreal taxa, and evidence of morphological convergence among arboreal lineages is observed. Taken together, these patterns suggest that arboreality has played a unique role in the evolution of this family, providing neither an evolutionary opportunity, nor an evolutionary dead end.

Most car manufacturers predict that in the first half of the next decade there will be fully autonomous vehicles on our roads. Such vehicles would have to communicate in order to mitigate problems caused by single-viewpoint approach. So there are a lot of researches and developments when it comes to communication layer of V2X (Vehicle-to-Everything), but there is still a lot to be done when it comes to data layer of this communication. This is why we propose using Semantic Web Technologies (SWT) to fill in gaps within data layer of V2X communication. By using SWT (Semantic Web Technologies) and Linked data, we plan to interconnect various data sources, in order to provide homogeneous way for connected autonomous vehicles (CAV) to access relevant information. Such information is currently contained in three distinctive type of sources. These are: Geo-stationary Static data sources (Maps, City models), Geostationary Dynamic data sources (IoT devices) and Non-geostationary Dynamic sources (Vehicles). Using SWT, our goal is to develop ontology(s), in such a way that in-vehicle algorithms can extract and process information about environment they are in, while taking into account available network bandwidth.

Metals present in concentrates are in a solid form and are not bioavailable, but they can dissolve or potentially transform to more soluble forms. Transformation/dissolution laboratory protocols have been developed to assess the importance of dissolution of sparingly soluble metal substances in the context of hazard classification; however, these tests represent worst-case scenarios for metal bioavailability because attenuation mechanisms such as complexation, sorption, and transport to the sediment are not considered. A unit world model (UWM) for metals in lakes, tableau input coupled kinetics equilibrium transport (TICKET)-UWM, has been developed that considers key processes affecting metal transport, fate, and toxicity including complexation by aqueous inorganic and ligands, partitioning to dissolved organic carbon (DOC) and particulate organic carbon (POC), precipitation, and transport of dissolved metals and solids between the water column and sediment. The TICKET-UWM model was used to assess the fate of a metal concentrate and dissolved metal ions released from the concentrate following an instantaneous input to a generalized lake. Concentrate dissolution rates in the water column were parameterized using results from batch transformation/dissolution tests for 2 specific concentrates containing lead (Pb), copper (Cu), and cobalt (Co). The TICKET-UWM results for a generalized lake environment showed that water column concentrations of metals in the lake environment after 28 d were several orders of magnitude lower than the 28-d concentration from the transformation/dissolution tests because Pb, Cu, and Co partitioned to POC in the water column and were subsequently removed due to settling. Resuspension of sediment served to increase total metal in the water column, but the resulting concentrations were still much lower than the 28-d concentrations from the transformation/dissolution tests. Information from TICKET-UWM could be used to refine the environmental hazard profiles of metals. Environ Toxicol Chem 2019;38:1256-1272. © 2019 SETAC.

Summary Normative data for vocal attack time (VAT) have previously been presented, but descriptive statistics and assessments of statistical significance of differences have previously been based on a data corpus that included both negative- and positive-valued VATs. Negative VAT values denote a glottal vocal attack, but, at the present time, the signification of the magnitude of a negative VAT value is unknown. The magnitude of a positive VAT value, on the other hand, conveys useful information about glottal behavior at the time of voice onset and is much more likely to be of use, especially in the clinical domain. We present descriptive statistics for the set of positive-valued VATs and demonstrate that the VAT differences between genders and among tone categories in Cantonese remain valid.

Indoor environmental quality (IEQ) affects occupants’ satisfaction, health, productivity, comfort, and well-being. IoT developments enable better monitoring of IEQ parameters; however, integrating the various types of heterogeneous data from both the IoT and BIM domains is cumbersome and capital intensive, and therefore, limits the potential of smart buildings. Semantic web technologies can reduce heterogeneity issues, which is necessary to facilitate complex IEQ models. An ontology integrating data related to a building’s topology and its static and dynamic properties is still lacking. The outline of this research is twofold. First, a systematic literature review was conducted to find state-of-the-art semantic web technologies related to building topology, static properties, and dynamic properties from the IoT and BIM domains. By graphically reviewing various ontologies, their valuable patterns, commonalities, and best practices were revealed. Secondly, those results were used to develop a new ontology that integrates topological building information with static and dynamic properties. This Building Performance Ontology (BOP) provides a generic upper-level description of properties and two lower-level ontologies representing observations and actuation. The ontology results in intuitive queries and is both horizontally and vertically extensible. Multiple levels of detail are introduced to ensure practical applicability and efficient patterns based on the data modeler’s needs. BOP opens up a new range of research opportunities in the IEQ domain.

Clustered regularly interspaced palindromic repeats (CRISPR)-associated (Cas)9 transactivating CRISPR RNAs (tracrRNAs) form distinct structures essential for target recognition and cleavage and dictate exchangeability between orthologous proteins. As noncoding RNAs that are often apart from the CRISPR array, their identification can be arduous. In this article, a new bioinformatic method for the detection of Cas9 tracrRNAs is presented. The approach utilizes a covariance model based on both sequence homology and predicted secondary structure to locate tracrRNAs. This method predicts a tracrRNA for 98% of CRISPR-Cas9 systems identified by us. To ensure accuracy, we also benchmark our approach against biochemically vetted tracrRNAs finding false-positive and false-negative rates of 5.5% and 7.1%, respectively. Finally, the association between Cas9 amino acid sequence-based phylogeny and tracrRNA secondary structure is evaluated, revealing strong evidence that secondary structure is evolutionarily conserved among Cas9 lineages. Altogether, our findings provide insight into Cas9 tracrRNA evolution and efforts to characterize the tracrRNA of Cas9 systems.

Highly polar chemicals are mobile in an aqueous environment. Analytical methods for these compounds in water are lacking. A combined target/nontarget screening method based on hydrophilic interaction LC coupled to high-resolution MS was developed. Thirty-two highly polar chemicals (including melem and melam) can thus be quantitatively measured in surface water and drinking water, and the MS data can be screened for unknown compounds. This is the first time a method for the determination of melem and melam in water has been described. The method is complementary to existing target and nontarget methods for less polar substances and can be applied for (drinking) water quality assessment. In a screening study in The Netherlands and Flanders, 12 of the 32 compounds were encountered in groundwater, surface water, and drinking water at levels between 0.01 and 4.2 μg/L. Concentrations in drinking water were compared with (provisional) guideline values to assess whether these may pose a concern for human health. In one drinking water sample, the concentration of dichloroacetic acid exceeded the provisional guideline value, indicating that health effects cannot be excluded on the basis of lifetime exposure. For most chemicals, reliable drinking water guideline values could not be derived due to the limited available of toxicity data.

High luminance light modules have been developed during the past few years based on luminescent concentrators. By using wavelength conversion, the etendue limitation that prohibits brightness increase of light that has been generated is removed, which is the principle of e.g. solar luminescent concentrators and the High Lumen Density (HLD) light engines developed for projection systems. While high-power LEDs are generally limited to a brightness of ca 200 Mnit (2 x 108 lm/m2sr), LED-pumped HLD modules have demonstrated brightness values of more than 1 Gnit. With these light sources requirements can be met for high flux applications with limited source size that are out of reach of LEDs. Such cases are found in e.g. stage and entertainment lighting or in front projection. So far, the luminescent concentrator light sources were based on single-crystalline (SC) converters. In this paper we report on the development of HLD light engines based on LED-pumped polycrystalline (PC) luminescent concentrators and simplified light source architectures. We demonstrate that with LuAG:Ce and LuYAG:Ce PC luminescent concentrators, emitting in the green-yellow spectral range, identical emission spectra and module performance characteristics can be achieved as with SC luminescent concentrators. This is successfully combined with improvements that were made with respect to HLD luminance and module efficacy. Key challenges for the PC luminescent converters are found in the minimization of light scattering. We conclude that with HLD modules based on PC concentrators, over 15 klm @

The document provides an overview of the development of a research plan to undertake the analyses of effect biomarkers in connection with exposure to the first set of priority substances in some of the aligned studies. A subset of the aligned studies was also identified to undertake analyses for exposure biomarkers for the 2nd set of priority chemicals.

Higher building performance saves operational costs, helps sustainability goals, and increases the comfort, satisfaction, productivity, and health of occupants. However, models simulating the occupants' perceived performance of indoor environments require highly heterogeneous input data. This paper aims to show how semantic web technologies can help to overcome problems deriving from this heterogeneity issue. Literature is studied to categorize the necessary input information for modeling occupants' perceived building performance. Two perspectives were consulted, namely the Indoor Environmental Quality approach and the Healing Environments approach. Based on the results, a core IEQ data model, integrating building topology, static properties, and dynamic properties, is proposed. We introduced a method to integrate this information by using the Building Performance Ontology (BOP). This method was tested by manually transforming the Open Smart Home (OSH) data to BOP vocabulary. Time-series data from various sensors were stored in InfluxDB and connected to the linked building data. A custom-built python tool was created to compute the thermal comfort of the OSH using the PMV/PPD method. The results indicate that a common data structure for static and dynamic properties helps to integrate the heterogeneity input data. Furthermore, we showed that adding occupants' data or system information could improve thermal comfort through multiple reactive approaches.

Objective As a follow-up to the first national survey of advance care planning uptake in New Zealand, which demonstrated a low level of plan completion, this study seeks to better understand the motivators and barriers associated with uptake. Methods Using a qualitative approach and a purposeful sampling method, nine interviewees participated in semi-structured interviews exploring in further depth their knowledge, attitudes and activities in relation to planning for end-of-life care. Thematic analysis was applied to the transcripts and several key themes identified. Results The five key themes were Knowledge of Advance Care Planning; Incomplete Planning; Relational Autonomy; Focus on Family; and Still Time to Plan. Conclusion A stepped process to encourage planning uptake is suggested, with legal and financial steps preceding the making of more personal values-based decisions salient to a serious diagnosis.