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Pesticides are a large and heterogenous group of chemicals with a complex geographic distribution in the environment. The purpose of this study was to explore the geographic distribution of pesticides in Danish drinking water and identify potential patterns in the grouping of pesticides. Our data included 899,169 analyses of 167 pesticides and metabolites, of which 55 were identified above the detection limit. Pesticide patterns were defined by (1) pesticide groups based on chemical structure and pesticide–metabolite relations and (2) an exploratory factor analysis identifying underlying patterns of related pesticides within waterworks. The geographic distribution was evaluated by mapping the pesticide categories for groups and factor components, namely those detected, quantified, above quality standards, and not analysed. We identified five and seven factor components for the periods 2002–2011 and 2012–2018, respectively. In total, 16 pesticide groups were identified, of which six were representative in space and time with regards to the number of waterworks and analyses, namely benzothiazinone, benzonitriles, organophosphates, phenoxy herbicides, triazines, and triazinones. Pesticide mapping identified areas where multiple pesticides were detected, indicating areas with a higher pesticide burden. The results contribute to a better understanding of the pesticide pattern in Danish drinking water and may contribute to exposure assessments for future epidemiological studies.

Ninna Hinchely Ebdrup,1– 3 Ulla Breth Knudsen,1,3 Jörg Schullehner,2,4 Linn Håkonsen Arendt,2,5 Zeyan Liew,6,7 Julie Lyngsø,2,5 Bjørn Bay,1,8 Pernille Jul Clemmensen,2 Torben Sigsgaard,2,9,10 Birgitte Hansen,4 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 2Department of Public Health, Aarhus University, Aarhus, Denmark; 3Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 4Geological Survey of Denmark and Greenland, Aarhus, Denmark; 5Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; 7Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA; 8Maigaard Fertility Clinic, Aarhus, Denmark; 9Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark; 10Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, DenmarkCorrespondence: Ninna Hinchely Ebdrup, Department of Obstetrics and Gynecology, Horsens Regional Hospital, Regionshospitalet Horsens, Sundvej 30, Horsens, 8700, Denmark, Tel +4528472111, Email ninebd@rm.dkPurpose: No studies have investigated if drinking water nitrate affects human fecundity. Experimental studies point at detrimental effects on fetal development and on female and male reproduction. This cohort study aimed to explore if female and male preconception and long-term exposure to nitrate in drinking water was associated with fecundability measured as time to pregnancy (TTP) or use of medically assisted reproduction (MAR) treatment.Methods: The study population consisted of pregnant women recruited in their first trimester in 1996– 2002 to the Danish National Birth Cohort. Preconception drinking-water nitrate exposure was estimated for the pregnant women (89,109 pregnancies), and long-term drinking water nitrate exposure was estimated from adolescence to conception for the pregnant women (77,474 pregnancies) and their male partners (62,000 pregnancies) by linkage to the national drinking water quality-monitoring database Jupiter. Difference in risk of TTP > 12 months or use of MAR treatment between five exposure categories and log-transformed continuous models of preconception and long-term nitrate in drinking water were estimated. Binominal regression models for risk ratios (RR) were adjusted for age, occupation, education, population density, and lifestyle factors.Results: Nitrate in drinking water (median preconception exposure: 1.9 mg/L; median long-term exposure: 3.3 mg/L) was not associated with TTP > 12 months or use of MAR treatment, neither in the categorical nor in the continuous models.Conclusion: We found no association between preconception or long-term exposure to drinking water nitrate and fecundability.Keywords: environmental pollutant, subfecundity, time to pregnancy, public health, groundwater

Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers’ residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization’s (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers' residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization's (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity.

Background Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. Methods We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. Results Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15–2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08–8.94)]. Conclusions The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.

Infertility is a worldwide health issue, but mechanisms of both male and female reproductive toxicity remain to be elucidated. So far, a limited focus has been on potentially harmful environmental factors such as arsenic, which is naturally occurring in groundwater. The objective of this review was to systematically investigate the association between arsenic in drinking water and adverse reproductive outcomes in men and women of fertile age. We conducted a systematic literature search and included case-control studies and cohort studies reporting on decreased semen quality characteristics, increased time to pregnancy, infertility, or spontaneous abortion. In total, 433 articles were screened and ultimately, eight studies were included. Included literature was quality assessed with the Newcastle-Ottawa Scale. Findings were reported in a narrative synthesis. Only one study investigated male fertility. An association between increasing arsenic exposure and decreasing semen quality characteristics was found, as well as an indication of arsenic accumulation in seminal plasma. These findings are, however, at high arsenic levels (>1000 µg/L). No consistent evidence was found to support the hypothesis that arsenic exposure from drinking water is a cause of longer waiting time to pregnancy or spontaneous abortion, being the only endpoints investigated in the included literature. In conclusion; the evidence is sparse and of varying quality, however, it does warrant attention, as it conflicts with existing evidence, mainly from cross-sectional or ecologic studies.

The Water Framework Directive (WFD) requires EU member states to assess the chemical status of groundwater bodies, a status defined according to threshold values for harmful elements and based on/the natural background level (NBL). The NBL is defined as the expected value of the concentration of elements naturally present in the environment. The aim of this study is to propose a methodology that will be broadly applicable to a wide range of conditions at the regional and national scale. Using a statistical approach, the methodology seeks to determine NBLs for SO4, As, Cd, Cr, Cu, Ni, Zn, and F based on the lithology of aquifers from which groundwater monitoring data were collected. The methodology was applied in six EU countries to demonstrate validity for a wide range of European regions. An average concentration was calculated for each parameter and chosen water point and linked to a lithology. Based on the dataset created, significant differences between lithologies and pressure categories (urban, agricultural, industrial, and mining) were tested using a nonparametric test. For each parameter, 90th percentiles were calculated to provide an estimation of the maximum natural concentrations possible for each lithology.

Determining natural background levels (NBLs) is a fundamental step in assessing the chemical status of groundwater bodies in the EU, as stipulated by the Water Framework and Groundwater Directives. The major challenges in deriving NBLs for trace metals are understanding the interaction of natural and anthropogenic processes and identifying the boundary between pristine and polluted groundwater. Thus, the purpose of this paper is to present a roadmap guiding the process of method selection for setting meaningful NBLs of trace metals in groundwater. To develop the roadmap, we compared and critically assessed how three methods for excluding polluted sampling points affect the NBLs for As, Cd, Cr, Cu, Ni, and Zn in Danish aquifers. These methods exclude sampling points based on (1) the primary use of the well (or sampling purpose), (2) the dominating anthropogenic pressure in the vicinity of the well, or (3) a combination of pollution indicators (NO3, pesticides, organic micropollutants). Except for Ni, the NBLs derived from the three methods did not differ significantly, indicating that the data pre-selection based on the primary use of the wells is an important step in assuring the removal of anthropogenically influenced points. However, this pre-selection could limit the data representativity with respect to the different groundwater types. The roadmap (a step-by-step guideline) can be used at the national scale in countries with varying data availability.

Pesticide pollution has raised public concern in Denmark due to potential negative health impacts and frequent findings of new substances after a recent expansion of the groundwater monitoring programme. Danish drinking water comes entirely from groundwater. Both the raw groundwater and the treated drinking water are regularly monitored, and the chemical analyses are reported to a publicly available national database (Jupiter). Based on these data, in this study we (1) provide a status of pesticide content in drinking water supplied by public waterworks in Denmark and (2) assess the proportion of Danish households exposed to pesticides from drinking water. ‘Pesticides’ here refers also to their metabolites, degradation and reaction products. The cleaned dataset represents 3004 public waterworks distributed throughout the country and includes 39 798 samples of treated drinking water analysed for 449 pesticides (971 723 analyses total) for the period 2002–2019. Of all these chemical analyses, 0.5% (n = 4925) contained a quantified pesticide (>0.03 μg/l). Pesticides were found at least once in the treated drinking water at 29% of all sampled public waterworks for the period 2002–2019 and at 21% of the waterworks for the recent period 2015–2019. We estimate that 56% of all Danish households were potentially exposed at least once to pesticides in drinking water at concentrations of 0.03–4.00 μg/l between 2002 and 2019. However, in 2015–2019, the proportion of the Danish households exposed to pesticides (0.03–4.00 μg/l) was 41%. The proportion of Danish households potentially exposed at least once to pesticides above the maximum allowed concentration (0.1 μg/l) according to the EU Drinking Water Directive (and the Danish drinking water standard) was 19% for 2002–2019 and 11% for 2015–2019. However, the maximum concentrations were lower than the World Health Organization’s compound-specific guidelines. Lastly, we explore data complexity and discuss the limitations imposed by data heterogeneity to facilitate future epidemiological studies.

BACKGROUND: There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark.METHODS: We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age.RESULTS: There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully-adjusted models. There was also some evidence of an exposure-response in models of continuous nitrate exposure and CNC.CONCLUSIONS: Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.

The hydrological relationship between surface waters and groundwaters in many regions of the world is well known and the effects of their mutual interaction and interaction with the soils and bedrocks, with respect to resulting changes in their chemical composition, are well studied. In this study we add to this knowledge by comparing the distributional patterns of strontium (Sr) isotopes in previously published 192 surface water samples with those of newly acquainted Sr isotope data from groundwater-based drinking water samples extracted from 163 of the major waterworks in Denmark. The aim is to investigate potential compositional changes that might derive from the interaction with the aquifer lithology or overlying sediments and soils. The average Sr isotope signatures of surface and groundwater-based drinking waters define 87Sr/86Sr values of 0.7096 ± 0.0015 (2σ) and 0.7088 ± 0.0013 (2σ), respectively. The skewed distribution of Sr isotope compositions in groundwaters towards lower 87Sr/86Sr values indicates enhanced contribution of natural carbonate-derived strontium with depth, while slightly elevated 87Sr/86Sr signatures in surface waters may reflect the diminished contribution of Sr from carbonates in the glaciogenic sediments due to their progressive acid dissolution. Strontium concentrations [Sr] in groundwater-based drinking water from the participating major waterworks define a country-wide average of 1.17 mg/L and the distributional pattern shows an East – West decreasing trend. Lowest concentrations are found in the West Jutland glaciogenic province (WJGP; average [Sr] = 0.36 mg/L) and in the northernmost tip of Jutland. A corresponding pattern, although less pronounced, is also depicted by the 87Sr/86Sr signatures of groundwater-based drinking water, whereby increasing 87Sr/86Sr values from Zealand through Funen into the Jutland peninsula correspond with increasing thickness of glaciogenic overburden providing (though mass-balance wise subordinate) radiogenic Sr to the natural carbonate-dominated groundwaters. The highest 87Sr/86Sr values are recorded in waters from northern Jutland, possibly reflecting the admixture of radiogenic strontium from late glacial and post-glacial glacio-isostatic adjustment-related marine aquifers. Generally, the surprisingly rather homogeneous and similar distributional patterns of 87Sr/86Sr signatures of Danish aquifers and surface waters implies a strong and dominant control of Sr by natural clastic (reworked) carbonate components in the Quaternary, Miocene and Holocene sediments, and to lesser degree (with the exception of northern central Jutland and Eastern Zealand) from the pre-Quaternary limestone dominated “basement” directly. Our results are consistent with a tight hydrological and geochemical interrelationship between surface waters and groundwaters in Denmark. There is a need for further investigations of the effects of advanced treatment of soft (acidic) groundwater-based drinking water on the concentrations and isotopic signatures of trace elements such as Sr. However, our study lends support for the adequate use of Sr isotope signatures of either of these waters to characterize the isotope compositional range of bioavailable fractions relevant for authenticity identification, forensic studies, and for prehistoric and modern human and animal proveniencing.

One in six couples experience fertility problems. Environmental factors may affect reproductive health; however, evidence is lacking regarding drinking water nitrates and outcomes of male and female fertility. The aim of this study was to investigate if exposure to nitrates in drinking water is associated with adverse reproductive outcomes in humans, and animals of fertile age. We conducted a systematic literature search and included case-control studies, cohort studies, and randomized control trials reporting on the association between drinking water nitrate exposure of men, women, or animals and adverse reproductive outcomes, specified as: Semen quality parameters, time to pregnancy (TTP), pregnancy rates, assisted reproductive technologies (ART), and spontaneous abortion. Findings were reported in a narrative synthesis. A total of 12 studies were included. The only human study included reported a decrease in spontaneous abortion at any detectable nitrate level. Overall, the 11 included animal studies support a potential negative effect on semen quality parameters but report equivocal results on TTP and number of offspring produced, and higher risk of spontaneous abortion. In conclusion, animal studies indicate possible effects on semen quality parameters and spontaneous abortion. However, with a few studies, including some with methodological limitations and small sample sizes, caution must be applied when interpreting these results.

Importance: Knowledge about the epidemiology of mental disorders in children and adolescents is essential for research and planning of health services. Surveys can provide prevalence rates, whereas population-based registers are instrumental to obtain precise estimates of incidence rates and risks.Objective: To estimate age- and sex-specific incidence rates and risks of being diagnosed with any mental disorder during childhood and adolescence.Design: This cohort study included all individuals born in Denmark from January 1, 1995, through December 31, 2016 (1.3 million), and followed up from birth until December 31, 2016, or the date of death, emigration, disappearance, or diagnosis of 1 of the mental disorders examined (14.4 million person-years of follow-up). Data were analyzed from September 14, 2018, through June 11, 2019.Exposures: Age and sex.Main Outcomes and Measures: Incidence rates and cumulative incidences of all mental disorders according to the ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, diagnosed before 18 years of age during the study period.Results: A total of 99 926 individuals (15.01%; 95% CI, 14.98%-15.17%), including 41 350 girls (14.63%; 95% CI, 14.48%-14.77%) and 58 576 boys (15.51%; 95% CI, 15.18%-15.84%), were diagnosed with a mental disorder before 18 years of age. Anxiety disorder was the most common diagnosis in girls (7.85%; 95% CI, 7.74%-7.97%); attention-deficit/hyperactivity disorder (ADHD) was the most common in boys (5.90%; 95% CI, 5.76%-6.03%). Girls had a higher risk than boys of schizophrenia (0.76% [95% CI, 0.72%-0.80%] vs 0.48% [95% CI, 0.39%-0.59%]), obsessive-compulsive disorder (0.96% [95% CI, 0.92%-1.00%] vs 0.63% [95% CI, 0.56%-0.72%]), and mood disorders (2.54% [95% CI, 2.47%-2.61%] vs 1.10% [95% CI, 0.84%-1.21%]). Incidence peaked earlier in boys than girls in ADHD (8 vs 17 years of age), intellectual disability (5 vs 14 years of age), and other developmental disorders (5 vs 16 years of age). The overall risk of being diagnosed with a mental disorder before 6 years of age was 2.13% (95% CI, 2.11%-2.16%) and was higher in boys (2.78% [95% CI, 2.44%-3.15%]) than in girls (1.45% [95% CI, 1.42%-1.49%]).Conclusions and Relevance: This nationwide population-based cohort study provides a first comprehensive assessment of the incidence and risks of mental disorders in childhood and adolescence. By 18 years of age, 15.01% of children and adolescents in this study were diagnosed with a mental disorder. The incidence of several neurodevelopmental disorders peaked in late adolescence in girls, suggesting possible delayed detection. The distinct signatures of the different mental disorders with respect to sex and age may have important implications for service planning and etiological research.

Planning for sustainable groundwater abstraction requires realistic and reliable assessments of groundwater drawdown in aquifers as well as impacted groundwater-dependent terrestrial and aquatic ecosystems. Present-day impact assessments allocate water for the environment and ecosystems in the form of environmental groundwater requirements (EGWRs). However, securing sustainable groundwater abstraction also requires stable groundwater quality for consumers and receptors (e.g. streams and groundwater-dependent ecosystems). We suggest dividing EGWR into two parts, namely EGWRflow, related to impacts on surface water, and EGWRwq, related to impacts on groundwater quality. We then propose a method for modelling maximum safe groundwater abstraction rates based on a relationship between water quality and piezometric heads. The method provides estimations of sustainable abstraction rates that secure stable water quality and maintain water security. Using hydrological modelling, we estimated spatially differentiated EGWRwq, for Zealand, Denmark, based on three different conditioned drawdowns of 3, 6 and 9 m. We found that depending on the boundaries and the different conditioned drawdowns EGWRwq poses a 2.5–83% share of the groundwater recharge. We found that a redistribution of water abstraction would make 27 million m3 available compared with actual abstraction, dependent on scale, while keeping within a conditioned drawdown of 3 m. Our results demonstrate how conditioned drawdown can be implemented with the objectives of evaluating actual abstraction and securing stable water quality, hence comprising a step towards more reliable and relevant groundwater impact assessments.

Background: Trihalomethanes (THMs) are widespread disinfection by-products (DBPs) in drinking water, and long-term exposure has been consistently associated with increased bladder cancer risk. Objective: We assessed THM levels in drinking water in the European Union as a marker of DBP exposure and estimated the attributable burden of bladder cancer. Methods: We collected recent annual mean THM levels in municipal drinking water in 28 European countries (EU28) from routine monitoring records. We estimated a linear exposure-response function for average residential THM levels and bladder cancer by pooling data from studies included in the largest international pooled analysis published to date in order to estimate odds ratios (ORs) for bladder cancer associated with the mean THM level in each country (relative to no exposure), population-attributable fraction (PAF), and number of attributable bladder cancer cases in different scenarios using incidence rates and population from the Global Burden of Disease study of 2016. Results: We obtained 2005-2018 THM data from EU26, covering 75% of the population. Data coverage and accuracy were heterogeneous among countries. The estimated population-weighted mean THM level was 11.7 μg/L [standard deviation (SD) of 11.2]. The estimated bladder cancer PAF was 4.9% [95% confidence interval (CI): 2.5, 7.1] overall (range: 0-23%), accounting for 6,561 (95% CI: 3,389, 9,537) bladder cancer cases per year. Denmark and the Netherlands had the lowest PAF (0.0% each), while Cyprus (23.2%), Malta (17.9%), and Ireland (17.2%) had the highest among EU26. In the scenario where no country would exceed the current EU mean, 2,868 (95% CI: 1,522, 4,060; 43%) annual attributable bladder cancer cases could potentially be avoided. Discussion: Efforts have been made to reduce THM levels in the European Union. However, assuming a causal association, current levels in certain countries still could lead to a considerable burden of bladder cancer that could potentially be avoided by optimizing water treatment, disinfection, and distribution practices, among other possible measures. https://doi.org/10.1289/EHP4495. This work was funded by the EU Seventh Framework Programme EXPOsOMICS Project (grant agreement no. 308610), Human Genetics Foundation agreement 17-080 ISG, and CIBER Epidemiología y Salud Pública (CIBERESP). ISGlobal is a member of the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya. We would like to thank the members of the European Programme for Intervention Epidemiology Training (EPIET) Alumni Network (EAN) for their assistance in identifying appropriate national focal points in specific countries. We would also like to thank the people from the national and local authorities and universities for the provision of THM data: Sofie Dewaele (Leefmilieu Brussel-BIM/Bruxelles Environnement–IBGE Afd. Inspectie en verontreinigde bodems, Dpt. Geïntegreerde controles, Brussels, Belgium), Steven Vanderwaeren (Team Watervoorziening-en gebruik, Vlaamse Milieumaatschappij, Afdeling Operationeel Waterbeheer, Brussels, Belgium), Jurica Štiglić (Croatian National Institute of Public Health, Zagreb, Croatia), Outi Zacheus (National Institute for Health and Welfare, Kuopio, Finland), Carmelo Massimo Maida (University of Palermo, Italy), Anna Norata (Agenzia di Tutela della Salute Citta’ Metropolitana Milano, Italy), Marco Chiesa (Agenzia di Tutela della Salute della Val Padana-Sede Territoriale di Mantova, Italy), Vincenzo Clasadonte (Agenzia di Tutela della Salute della Val Padana-Sede Territoriale Cremona, Italy), Emilia Guberti (Local Health Authority, Bologna, Italy), Cinzia Govoni (Local Health Authority, Ferrara, Italy), Paolo Pagliai (Local Health Authority Romagna, Italy), Daniela de Vita (Local Health Authority, Reggio Emilia, Italy), Danila Tortorici (Regional Health and Social Agency, Emilia Romagna, Italy), Marco Schintu (University of Cagliari, Italy), Paolo Montuori (University of Napoli Federico II, Italy), Audrius Dedele (Department of Environmental Sciences, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas, Lithuania), Stefan Cachia (Water Services Corporation, Malta), Roel C.H. Vermuelen (Institute of Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands), the Chief Sanitary Inspectorate (Poland), Luís Simas (Water Quality Department, Entidade Reguladora, Dos Serviços De Águas e Resíduos, Lisboa, Portugal), and Christina Forslund (Food Control Department, National Food Agency, Uppsala, Sweden). Finally, we would like to thank Charles F. Lynch (University of Iowa, USA), Sylvaine Cordier (Université de Rennes, Inserm, École des hautes études en santé Publique (EHESP), Rennes, France), Will D. King (Queen’s University, Kingston, Ontario, Canada), and Kenneth P. Cantor (National Cancer Institute, National Institutes of Health, Bethesda, USA) for allowing us to use the dose–exposure data from their study. We are grateful to Xavier Basagaña (ISGlobal) for statistical assistance.

rsenic in drinking water is a global health concern. The WHO guideline of 10 µg/L is considered provisional and WHO recommends that concentrations should be as low as possible. High income, low dose countries have a unique opportunity to lower arsenic concentrations in drinking water. The question, however, is how to achieve this goal. Simply legislating a low criterion may not be an adequate solution. In a case study from Denmark, the effects of lowering the criterion to 5 µg/L was followed over more than a decade. Results showed a wide variety of responses from the more than 100 waterworks that were thrown into non-compliance.

Objectives: To assess whether exposure to specific classes of neuroactive non-organochlorine insecticides is associated with diabetes mellitus or related metabolic traits. Methods: Eligibility criteria: Any type of epidemiological and human exposure studies providing an exposure contrast to neuroactive non-organochlorine insecticides and a measure of association to diabetes mellitus or related metabolic traits. We will include published peer-reviewed studies in both English and non-English language.Information sources: Articles will be located in the NCBI PubMed, Embase, Scopus, Web of Science and LILACS databases, supplemented with manual searching of reference lists and articles citing the included studies.Risk of bias assessment: Risk of bias in individual studies will be assessed using tools from the Navigation Guide systematic review methodology, while the risk of bias at the outcome level will be assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines.Data synthesis and analysis: When studies are sufficiently similar in population, exposure, comparator and effect estimate to meaningfully allow quantitative synthesis, we will perform meta-analysis. Otherwise, results will be summarized qualitatively. Funding: The authors are paid employees of their respective institutions. MRHH is a Ph.D. student working under grants from Aarhus University and the National Research Centre for the Working Environment. Registration: PROSPERO CRD42017068861. Keywords: Diabetes mellitus, Blood glucose, Hyperglycaemia, Pesticide, Insecticide

The naturally occurring geogenic elements iodine (I), lithium (Li), and strontium (Sr) have a beneficial effect on human health. Iodine has an essential role in human metabolism while Li and Sr are used, respectively, as a treatment for various mental disorders and for post-menopausal osteoporosis. The aim here is to evaluate the potential for future epidemiological investigations in Denmark of lifelong and chronic exposure to low doses of these compounds. The drinking water data represents approximately 45% of the annual Danish groundwater abstraction for drinking water purposes, which supplies approximately 2.5 million persons. The spatial patterns were studied using inverse distance weighted interpolation and cluster analysis. The exposed population was estimated based on two datasets: (1) population density in the smallest census unit, the parishes, and (2) geocoded addresses where at least one person is residing. We found significant spatial variation in the exposure for all three elements, related mainly to geochemical processes. This suggests a prospective opportunity for future epidemiological investigation of long-term effects of I, Li, and Sr, either alone or in combinations with other geogenic elements such as Ca, Mg or F.

Suicide is a major public health concern. High-dose lithium is used to stabilize mood and prevent suicide in patients with affective disorders. Lithium occurs naturally in drinking water worldwide in much lower doses, but with large geographical variation. Several studies conducted at an aggregate level have suggested an association between lithium in drinking water and a reduced risk of suicide; however, a causal relation is uncertain. Individual-level register-based data on the entire Danish adult population (3.7 million individuals) from 1991 to 2012 were linked with a moving five-year time-weighted average (TWA) lithium exposure level from drinking water hypothesizing an inverse relationship. The mean lithium level was 11.6 μg/L ranging from 0.6 to 30.7 μg/L. The suicide rate decreased from 29.7 per 100,000 person-years at risk in 1991 to 18.4 per 100,000 person-years in 2012. We found no significant indication of an association between increasing five-year TWA lithium exposure level and decreasing suicide rate. The comprehensiveness of using individual-level data and spatial analyses with 22 years of follow-up makes a pronounced contribution to previous findings. Our findings demonstrate that there does not seem to be a protective effect of exposure to lithium on the incidence of suicide with levels below 31 μg/L in drinking water.

Accurate assessments of exposure to nitrate in drinking water is a crucial part of epidemiological studies investigating long-term adverse human health effects. However, since drinking water nitrate measurements are usually collected for regulatory purposes, assumptions on (1) the intra-distribution system variability and (2) short-term (seasonal) concentration variability have to be made. We assess concentration variability in the distribution system of nitrate, nitrite, and ammonium, and seasonal variability in all Danish public waterworks from 2007 to 2016. Nitrate concentrations at the exit of the waterworks are highly correlated with nitrate concentrations within the distribution net or at the consumers' taps, while nitrite and ammonium concentrations are generally lower within the net compared with the exit of the waterworks due to nitrification. However, nitrification of nitrite and ammonium in the distribution systems only results in a relatively small increase in nitrate concentrations. No seasonal variation for nitrate, nitrite, or ammonium was observed. We conclude that nitrate measurements taken at the exit of the waterworks are suitable to calculate exposures for all consumers connected to that waterworks and that sampling frequencies in the national monitoring programme are sufficient to describe temporal variations in longitudinal studies.

Importance: Results from animal and human studies suggest that lithium in therapeutic doses may improve learning and memory and modify the risk of developing dementia. Additional preliminary studies suggest that subtherapeutic levels, including microlevels of lithium, may influence human cognition.Objective: To investigate whether the incidence of dementia in the general population covaries with long-term exposure to microlevels of lithium in drinking water.Design, Setting, and Participants: This Danish nationwide, population-based, nested case-control study examined longitudinal, individual geographic data on municipality of residence and data from drinking water measurements combined with time-specific data from all patients aged 50 to 90 years with a hospital contact with a diagnosis of dementia from January 1, 1970, through December 31, 2013, and 10 age- and sex-matched control individuals from the Danish population. The mean lithium exposure in drinking water since 1986 was estimated for all study individuals. Data analysis was performed from January 1, 1995, through December 31, 2013.Main Outcomes and Measures: A diagnosis of dementia in a hospital inpatient or outpatient contact. Diagnoses of Alzheimer disease and vascular dementia were secondary outcome measures. In primary analyses, distribution of lithium exposure was compared between patients with dementia and controls.Results: A total of 73 731 patients with dementia and 733 653 controls (median age, 80.3 years; interquartile range, 74.9-84.6 years; 44 760 female [60.7%] and 28 971 male [39.3%]) were included in the study. Lithium exposure was statistically significantly different between patients with a diagnosis of dementia (median, 11.5 µg/L; interquartile range, 6.5-14.9 µg/L) and controls (median, 12.2 µg/L; interquartile range, 7.3-16.0 µg/L; P Conclusions and Relevance: Long-term increased lithium exposure in drinking water may be associated with a lower incidence of dementia in a nonlinear way; however, confounding from other factors associated with municipality of residence cannot be excluded.

Objective Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder. Methods We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals. Results The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 μg/L; interquartile range [IQR]: 7.9-15.5 μg/L) and controls (12.5 μg/L; IQR: 7.6-15.7 μg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age). Conclusion Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark.

Importance of work and objectivesStudies have suggested that nitrate in drinking water increased the risk of colorectal cancer. However, often exposure estimations and study size were insufficient to yield unequivocal results. We addressed these challenges by conducting a detailed exposure assessment of the entire Danish population.MethodologiesGIS methods were used to assign nitrate concentrations at the waterworks to the 2,779 water supply areas and 55,752 private wells. Annual nitrate concentrations were assigned to each resident of Denmark from 1978-2012, based on their exact address in the Civil Registration System. For each person the individual adult exposure (age 20-35) was calculated. Information on colon and rectal cancer diagnoses was obtained from the national Cancer Registry. Cox proportional hazard models using age as time scale were fit to assess the risk within exposure deciles. Possible confounding co-variates, such as sex, education, region and previous cancer diagnoses were included and sensitivity analyses conducted taking the uncertainty of the exposure estimate into account.Main results2,833,825 individuals were enrolled, totaling a follow-up time of approx. 32 million person-years. Preliminary results will be presented, indicating an increased risk for colon cancer at concentrations far below the drinking water standard (50 mg/l). Results for rectal cancer did not show the same consistent pattern.ConclusionsThis nationwide population-based study addresses previous studies’ challenges of poor exposure assessment and insufficient study population sizes. It adds to the increasing body of evidence of negative chronic health effects associated with increased levels of nitrate in drinking water. Importance of work and objectivesStudies have suggested that nitrate in drinking water increased the risk of colorectal cancer. However, often exposure estimations and study size were insufficient to yield unequivocal results. We addressed these challenges by conducting a detailed exposure assessment of the entire Danish population.MethodologiesGIS methods were used to assign nitrate concentrations at the waterworks to the 2,779 water supply areas and 55,752 private wells. Annual nitrate concentrations were assigned to each resident of Denmark from 1978-2012, based on their exact address in the Civil Registration System. For each person the individual adult exposure (age 20-35) was calculated. Information on colon and rectal cancer diagnoses was obtained from the national Cancer Registry. Cox proportional hazard models using age as time scale were fit to assess the risk within exposure deciles. Possible confounding co-variates, such as sex, education, region and previous cancer diagnoses were included and sensitivity analyses conducted taking the uncertainty of the exposure estimate into account.Main results2,833,825 individuals were enrolled, totaling a follow-up time of approx. 32 million person-years. Preliminary results will be presented, indicating an increased risk for colon cancer at concentrations far below the drinking water standard (50 mg/l). Results for rectal cancer did not show the same consistent pattern.ConclusionsThis nationwide population-based study addresses previous studies’ challenges of poor exposure assessment and insufficient study population sizes. It adds to the increasing body of evidence of negative chronic health effects associated with increased levels of nitrate in drinking water.

This study discusses 1) the national legislative frameworks, terminologies, and criteria for the recognition of natural mineral waters and thermal waters in selected European countries (Austria, Bosnia and Herzegovina, Denmark, France, Hungary, Iceland, Italy, Lithuania, Poland, Portugal, Romania, Serbia, Slovenia, and Spain), and 2) it provides a first extensive multi-national overview of hydrogeological and hydrogeochemical characteristics of numerous water sources from those regions. Natural mineral waters are well defined and regulated in the European Union by the Directives 2009/54/EC and 2003/40/EC that are implemented by national law regulations. In contrast, no legal definition exists for thermal waters on an EU level and national definitions commonly differ or are not present. Defining thermal waters by water temperatures of at least 20 °C at the outlet is commonly found (6 out of 15 countries), but other definitions like considering the difference to the average air temperature are also present. Furthermore, no definitions on a national level are quite frequent (5 out of 15 countries), those countries preferentially refer to expert recognitions. We considered 678 natural mineral waters and 2,390 thermal waters in this study and collected information on practical use, hydrogeological settings and hydrogeochemical conditions. The comparison of the datasets shows commonalities like a predominance porous aquifers, especially sandy aquifers, and sedimentary carbonate rock aquifers (limestone, dolomite, chalk). Furthermore, natural mineral waters commonly show TDS contents of less than 1 g/l and alkaline-earth-HCO3 water types. Surprisingly, 21 % of the considered sources bear water temperatures above 20 °C and could be considered as thermal waters as well. Thermal waters – the majority (above 30 °C) is found in Hungary - usually show water temperatures between 20 and 70 °C and TDS contents between 1 and 14.5 g/l. The hydrogeochemical properties show a larger variation in contrast to natural mineral waters, but Na-(HCO3, Cl) waters seem to be most commonly found.