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Exposure to Perfluoroalkyl acids (PFAS) can impair human reproductive function, e.g., by delaying or advancing puberty, although their mechanisms of action are not fully understood. We therefore set out to evaluate the relationship between serum PFAS levels, both individually and as a mixture, on the Hypothalamic-Pituitary-Gonadal (HPG) axis by analyzing serum levels of reproductive hormones and also kisspeptin in European teenagers participating in three of the HBM4EU Aligned Studies. For this purpose, PFAS compounds were measured in 733 teenagers from Belgium (FLEHS IV study), Slovakia (PCB cohort follow-up), and Spain (BEA study) by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) in laboratories under the HBM4EU quality assurance quality control (QA/QC) program. In the same serum samples, kisspeptin 54 (kiss-54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were also measured using immunosorbent assays. Sex-stratified single pollutant linear regression models for separate studies, mixed single pollutant models accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the mixture of the three most available (PFNA, PFOA, and PFOS) were fit. PFAS associations with reproductive markers differed according to sex. Each natural log-unit increase of PFOA, PFNA, and PFOS were associated with higher TT [18.41 (6.18; 32.31), 15.60 (7.25; 24.61), 14.68 (6.18; 24.61), respectively] in girls, in the pooled analysis (all studies together). In males, G-computation showed that PFAS mixture was associated with lower FSH levels [-10.51 (−18.81;-1.36)]. The BKMR showed the same patterns observed in G-computation, including a significant increase on male Kiss-54 and SHBG levels. Overall, effect biomarkers may enhance the current epidemiological knowledge regarding the adverse effect of PFAS in human HPG axis, although further research is warranted. [Display omitted] • The relationship of PFAS, reproductive hormones and kiss-54 levels was investigated. • Some PFAS were associated with higher TT levels in females. • The PFAS mixture (PFOA, PFOS, PFNA) showed the same trends in female. • PFAS were associated with lower hormones and higher SHBG in males. • PFAS mixture was also associated with higher kiss-54 in males. [ABSTRACT FROM AUTHOR]

Toxicological risk assessment of contaminants of emerging concern (CEC) in (sources of) drinking water is required to identify potential health risks and prioritize chemicals for abatement or monitoring. In such assessments, concentrations of chemicals in drinking water or sources are compared to either (i) health-based (statutory) drinking water guideline values, (ii) provisional guideline values based on recent toxicity data in absence of drinking water guidelines, or (iii) generic drinking water target values in absence of toxicity data. Here, we performed a toxicological risk assessment for 163 CEC that were selected as relevant for drinking water. This relevance was based on their presence in drinking water and/or groundwater and surface water sources in downstream parts of the Rhine and Meuse, in combination with concentration levels and physicochemical properties. Statutory and provisional drinking water guideline values could be derived from publically available toxicological information for 142 of the CEC. Based on measured concentrations it was concluded that the majority of substances do not occur in concentrations which individually pose an appreciable human health risk. A health concern could however not be excluded for vinylchloride, trichloroethene, bromodichloromethane, aniline, phenol, 2-chlorobenzenamine, mevinphos, 1,4-dioxane, and nitrolotriacetic acid. For part of the selected substances, toxicological risk assessment for drinking water could not be performed since either toxicity data (hazard) or drinking water concentrations (exposure) were lacking. In absence of toxicity data, the Threshold of Toxicological Concern (TTC) approach can be applied for screening level risk assessment. The toxicological information on the selected substances was used to evaluate whether drinking water target values based on existing TTC levels are sufficiently protective for drinking water relevant CEC. Generic drinking water target levels of 37 μg/L for Cramer class I substances and 4 μg/L for Cramer class III substances in drinking water were derived based on these CEC. These levels are in line with previously reported generic drinking water target levels based on original TTC values and are shown to be protective for health effects of the majority of contaminants of emerging concern evaluated in the present study. Since the human health impact of many chemicals appearing in the water cycle has been studied insufficiently, generic drinking water target levels are useful for early warning and prioritization of CEC with unknown toxicity in drinking water and its sources for future monitoring. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: The biocide and environmental pollutant bis(tri-n-butyltin)oxide (TBTO) causes thymus atrophy in rodents. Whether the depletion of thymic lymphocytes by tributyltin compounds may be the result of inhibition of cell proliferation or induction of apoptosis is subject of debate. We examined gene expression profiles in primary rat thymocytes exposed to TBTO in vitro at dose levels of 0, 0.1, 0.3, 0.5, and 1.0μM. By measuring cell viability and apoptosis, exposure conditions were selected that would provide information on changes in gene expression preceding or accompanying functional effects of TBTO. Several processes related to TBTO-induced toxicity were detected at the transcriptome level. Effects on lipid metabolisms appeared to be the first indication of disruption of cellular function. Many transcriptional effects of TBTO at higher dose levels were related to apoptotic processes, which corresponded to present or subsequent thymocyte apoptosis observed phenotypically. The gene expression profile was, however, not unambiguous since expression of apoptosis-related genes was both increased and decreased. Stimulation of glucocorticoid receptor signaling appeared to be a relevant underlying mechanism of action. These findings suggest that TBTO exerts its toxic effects on the thymus primarily by affecting apoptotic processes, but the possibility is discussed that this may in fact represent an early effect that precedes inhibition of cell proliferation. At the highest dose level tested, TBTO additionally repressed mitochondrial function and immune cell activation. Our in vitro toxicogenomics approach thus identified several cellular and molecular targets of TBTO that may mediate the toxicity towards thymocytes and thereby its immunosuppressive effects. [Copyright &y& Elsevier]

Abstract: Lactic acid bacteria are claimed to have immunomodulating effects. Stimulation as well as suppression of T helper (Th)1 mediated immune responses, have been described for various strains. Experiments involving Lactobacillus casei Shirota (LcS) detected mainly enhancement of innate immune responses and promotion of Th1 mediated immune reactivity. To confirm and further investigate modulation of Th1 responses and development of autoimmune disease by LcS, the consequences of oral administration of LcS were assessed in several experiments. The effect of LcS varied between the different models. No modulation was found in the mitogen-induced cell proliferation and cytokine release assays in mesenteric lymph nodes of Wistar rats. LcS inhibited the Th1 mediated immune response in an adapted murine Local Lymph Node Assay (LLNA) in BALB/c mice, whereas experimental autoimmune encephalomyelitis (EAE) in Lewis rats was aggravated. These varying effects on Th1 responses indicate that beneficial as well as harmful effects on immune related disorders could occur after LcS consumption. Since microarray analysis is suggested to be more sensitive and predictive than functional tests, gene expression profiling was included as an alternative endpoint in the testing of immunomodulation. The detected gene expression profiles did not reflect the effects of LcS on the immune system. Microarray analysis may therefore have no more predictive value than immune function assays when investigating immunomodulation by probiotics. To gain further insight into effects of probiotics on immune function, experiments including cytokine assays and gene expression analysis combined with disease models could be useful. [Copyright &y& Elsevier]

Abstract: The murine local lymph node assay (LLNA) was originally developed as a predictive test method for the identification of chemicals with sensitizing potential. In this study we demonstrated that an adapted LLNA can also be used as an immune function assay by studying the effects of orally administered immunomodulating compounds on the T-cell-dependent immune response induced by the contact sensitizer 2,4-dinitrochlorobenzene (DNCB). C57Bl/6 mice were treated with the immunotoxic compounds cyclosporin A (CsA), bis(tri-n-butyltin)oxide (TBTO) or benzo[a]pyrene, (B[a]P). Subsequently, cell proliferation and interferon-γ (IFN-γ) and interleukin (IL)-4 release were determined in the auricular lymph nodes (LNs) after DNCB application on both ears. Immunosuppression induced by CsA, TBTO and B[a]P was clearly detectable in this application of the LLNA. Cytokine release measurements proved valuable to confirm the results of the cell proliferation assay and to obtain an indication of the effect on Th1/Th2 balance. We believe to have demonstrated the applicability of an adapted LLNA as an immune function assay in the mouse. [Copyright &y& Elsevier]

Graphical abstract Highlights • Visualization of ToxCast data availability and density, including water relevant mechanisms of toxicity. • Efficient prioritization strategy for suspect screening data combining occurrence and hazard data. • High throughput approach allows automation. • Little overlap between exposure only and exposure/hazard ratio based prioritization. Abstract Advancements in high-resolution mass spectrometry based methods have enabled a shift from pure target analysis to target, suspect and non-target screening analyses to detect chemicals in water samples. The multitude of suspect chemicals thereby detected needs to be prioritized for further identification, prior to health risk assessment and potential inclusion into monitoring programs. Here, we compare prioritization of chemicals in Dutch water samples based on relative intensities only to prioritization including hazard information based on high-throughput in vitro toxicity data. Over 1000 suspects detected in sewage treatment plant effluent, surface water, groundwater and drinking water samples were ranked based on their relative intensities. Toxicity data availability and density in the ToxCast database were determined and visualized for these suspects, also in regard to water relevant mechanisms of toxicity. More than 500 suspects could be ranked using occurrence/hazard ratios based on more than 1000 different assay endpoints. The comparison showed that different prioritization strategies resulted in significantly different ranking, with only 2 suspects prioritized based on occurrence among the top 20 in the hazard ranking. We therefore propose a novel scheme that integrates both exposure and hazard data, and efficiently prioritizes which features need to be confidently identified first. [ABSTRACT FROM AUTHOR]

The present study explores the ToxCast/Tox21 database to select candidate bioassays as bioanalytical tools for measuring groups of chemicals in water. To this aim, the ToxCast/Tox21 database was explored for bioassays that detect polycyclic aromatic hydrocarbons (PAHs), aromatic amines (AAs), (chloro)phenols ((C)Ps) and halogenated aliphatic hydrocarbons (HAliHs), which are included in the European and/or Dutch Drinking Water Directives. Based on the analysis of the availability and performance of bioassays included in the database, we concluded that several bioassays are suitable as bioanalytical tools for assessing the presence of PAHs and (C)Ps in drinking water sources. No bioassays were identified for AAs and HAliHs, due to the limited activity of these chemicals and/or the limited amount of data on these chemicals in the database. A series of bioassays was selected that measure molecular or cellular effects that are covered by bioassays currently in use for chemical water quality monitoring. Interestingly, also bioassays were selected that represent molecular or cellular effects that are not covered by bioassays currently applied. The usefulness of these newly identified bioassays as bioanalytical tools should be further evaluated in follow-up studies. Altogether, this study shows how exploration of the ToxCast/Tox21 database provides a series of candidate bioassays as bioanalytical tools for measuring groups of chemicals in water. This assessment can be performed for any group of chemicals of interest (if represented in the database), and may provide candidate bioassays that can be used to complement the currently applied bioassays for chemical water quality assessment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Cohort of 7 million individuals: one of the largest studies in drinking water epidemiology. • Magnesium in drinking water associated with reduced risk for coronary heart disease mortality. • Calcium below 30 mg/L associated with elevated risk for coronary heart disease mortality. • No protective effect of calcium, magnesium, or hardness on cardiovascular disease mortality. • Nitrate in drinking water not related to mortality due to colorectal cancer. Although drinking water in the Netherlands is generally accepted as safe, public concern about health risks of long-term intake still exist. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to answer policy-relevant questions and safeguard an efficient science-to-policy transfer of results. Human internal exposure levels were assessed using two data sets from all European regions and Israel. The first collated existing human biomonitoring (HBM) data (2005–2019). The second consisted of new data generated in the harmonized "HBM4EU Aligned Studies" (2014–2021) on children and teenagers for the ten most relevant phthalates and DINCH, accompanied by a quality assurance/quality control (QA/QC) program for 17 urinary exposure biomarkers. Exposures differed between countries, European regions, age groups and educational levels. Toxicologically derived Human biomonitoring guidance values (HBM-GVs) were exceeded in up to 5% of the participants of the HBM4EU Aligned Studies. A mixture risk assessment (MRA) including five reprotoxic phthalates (DEHP, DnBP, DiBP, BBzP, DiNP) revealed that for about 17% of the children and teenagers, health risks cannot be excluded. Concern about male reproductive health emphasized the need to include other anti-androgenic substances for MRA. Contaminated food and the use of personal care products were identified as relevant exposure determinants paving the way for new regulatory measures. Time trend analyses verified the efficacy of regulations: especially for the highly regulated phthalates exposure dropped significantly, while levels of the substitutes DINCH and DEHTP increased. The HBM4EU e-waste study, however, suggests that workers involved in e-waste management may be exposed to higher levels of restricted phthalates. Exposure-effect association studies indicated the relevance of a range of endpoints. A set of HBM indicators was derived to facilitate and accelerate science-to-policy transfer. Result indicators allow different groups and regions to be easily compared. Impact indicators allow health risks to be directly interpreted. The presented results enable successful science-to-policy transfer and support timely and targeted policy measures. • First comprehensive European HBM exposure data on phthalates and substitute plasticizers. • Pronounced phthalate exposure reduction verifies the effectiveness of policy measures. • Still, for 17% of the children and teenagers health risks cannot be excluded based on mixture risk assessment. • Contaminated food and use of personal care products are key exposure determinants. • Successful science-to-policy transfer supports timely and targeted policy measures. [ABSTRACT FROM AUTHOR]

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. Unlabelled Image • Lack of European hydraulic fracturing related water assessments • Chemical and bioassay assessment of Dutch hydraulic fracturing related water samples • Fracturing/flowback fluids potentially pose human and environmental health concerns. • Clear genotoxic and oxidative stress responses found for fracturing/flowback fluids • Measures justified to handle, transport and treat fracturing/flowback fluids. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

UV/H 2 O 2 processes in drinking water treatment may generate byproducts which cause an increased response in Ames fluctuation assays. As this probably involves a mixture of substances in very low concentrations, it is challenging to identify the individual byproducts. Therefore it was studied under which conditions mutagenic byproducts are formed and how this can be prevented. It was found that positive Ames fluctuation test responses only are obtained when Medium Pressure UV lamps are used, and not with Low Pressure lamps. This probably is explained by the photolysis of nitrate, which plays an important role in the formation of mutagenic byproducts. The most important parameters involved in the formation of such byproducts were demonstrated to be the nitrate concentration, the natural organic matter, the UV spectrum of the lamps, and the UV dose applied. These factors explain up to 74–87% of the Ames fluctuation test responses after UV/H 2 O 2 drinking water treatment. By taking this into account, drinking water utilities can estimate whether UV processes applied in their case may cause the formation of mutagenic byproducts, and how to take measures to prevent it. [ABSTRACT FROM AUTHOR]