Perfluorooctane Sulfonamide Induced Autotoxic Effects on the Zebrafish Immune System.

Perfluorooctane sulfonamide (PFOSA) is an immediate perfluorooctanesulfonate (PFOS) precursor (PreFOS). Previous studies have shown PFOSA to induce stronger toxic responses compared to other perfluorinated compounds (PFCs). However, the specific nature of PFOSA-induced toxicity, whether autonomous or mediated by its metabolite PFOS, has not been fully elucidated. This study systematically investigates the immunomodulatory effects of PFOSA and PFOS in zebrafish (Danio rerio). Exposure to PFOSA compromised the zebrafish's ability to defend against pathogenic infections, as evidenced by increased bacterial adhesion to their skin and reduced levels of the biocidal protein lysozyme (LYSO). Moreover, PFOSA exposure was associated with disruptions in inflammatory markers and immune indicators, along with a decrease in immune cell counts. The findings from this study suggest that the immunotoxicity effects of PFOSA are primarily due to its own toxicity rather than its metabolite PFOS. This conclusion was supported by dose-dependent responses, the severity of observed effects, and multivariate analysis. In addition, our experiments using NF-κB-morpholino knock-down techniques further confirmed the role of the Nuclear factor-κappa B pathway in mediating PFOSA-induced immunotoxicity. In conclusion, this study reveals that PFOSA impairs the immune system in zebrafish through an autotoxic mechanism, providing valuable insights for assessing the ecological risks of PFOSA.

Assessment of spatiotemporal risks for nationwide groundwater nitrate contamination.

National assessments of groundwater contamination risks are crucial for sustaining high-quality groundwater supplies. However, traditional methods often treat groundwater contamination risk as a steady-state indicator without considering spatiotemporal variation in risk-both geographically and over time- caused by anthropogenic and climate influences. In this work, XGBoost, a tree-based algorithm, was applied to comprehensively analyze the drivers of groundwater contamination from nitrate, using data on13 physical features (as used by the index-based ranking method DRASTIC) and 30 anthropogenic features from 1985 to 2010 in the contiguous United States (CONUS). The results indicate that physical features controlling the transport processes, particularly those affecting contaminant travel time from land surface to groundwater (depth to water table and transmissivity), were the dominant factors for nitrate contamination in groundwater. This was followed by features representing the potential nitrogen loading. Positive correlations between most features and nitrogen loading years were found, suggesting their growing influence on contamination risk. Based on the drivers identified for nitrate concentrations exceeding 10 mg/L in groundwater and their varying temporal contributions, this study proposes a reformulated index-based method for contamination risk assessment. With this method an overall accuracy of around 70 % was achieved based on the validation data set. The predicted high-risk areas are mainly intensive irrigation regions, such as the High Plains, northern Midwest, and Central Valley. This new approach contributes to a more accurate and effective assessment of the contamination risks of groundwater on a regional and national scale under temporally varying environmental conditions.

Limits, challenges, and opportunities of sampling groundwater wells with plastic casings for microplastic investigations.

Investigating microplastics (MPs) in groundwater suffers from problems already faced by surface water research, such as the absence of common protocols for sampling and analysis. While the use of plastic instruments during the collection, processing, and analysis of water samples is usually avoided in order to minimize unintentional contamination, groundwater research encompassing MPs faces unique challenges. Groundwater sampling typically relies on pre-existing monitoring wells (MWs) and water wells (WWs) that are often constructed with polyvinyl chloride (PVC) casings or pipes due to their favorable price-performance ratio. Despite the convenience, however, the suitability of PVC casings for MP research is questionable. Unfortunately, the specifics of these wells are often not detailed in published studies. Current literature does not indicate significant pollution risks from PVC casings, suggesting these wells might still be viable for MP studies. Our preliminary analysis of the existing literature indicates that if PVC exceeds 6 % of the total MP concentration, it is likely that casings and pipes made of PVC are a source of pollution. Above this threshold, additional investigations in MWs and WWs with PVC casings and pipes are suggested.

Application of single-cell Raman-deuterium isotope probing to reveal the resistance of marine ammonia-oxidizing archaea SCM1 against common antibiotics.

Antimicrobial resistance (AMR) in oceans poses a significant threat to human health through the seafood supply chain. Ammonia-oxidizing archaea (AOA) are important marine microorganisms and play a key role in the biogeochemical nitrogen cycle around the world. However, the AMR of marine AOA to aquicultural antibiotics is poorly explored. Here, Raman-deuterium isotope probing (Raman-DIP), a single-cell tool, was developed to reveal the AMR of a typical marine species of AOA, Nitrosopumilus maritimus (designated SCM1), against six antibiotics, including erythromycin, tetracycline, novobiocin, neomycin, bacitracin, and vancomycin. The D2O concentration (30% v/v) and culture period (9 days) were optimized for the precise detection of metabolic activity in SCM1 cells through Raman-DIP. The relative metabolic activity of SCM1 upon exposure to antibiotics was semi-quantitatively calculated based on single-cell Raman spectra. SCM1 exhibited high resistance to erythromycin, tetracycline, novobiocin, neomycin, and vancomycin, with minimum inhibitory concentration (MIC) values between 100 and 400 mg/L, while SCM1 is very sensitive to bacitracin (MIC: 0.8 mg/L). Notably, SCM1 cells were completely inactive under the metabolic activity minimum inhibitory concentration conditions (MA-MIC: 1.6-800 mg/L) for the six antibiotics. Further genomic analysis revealed the antibiotic resistance genes (ARGs) of SCM1, including 14 types categorized into 33 subtypes. This work increases our knowledge of the AMR of marine AOA by linking the resistant phenome to the genome, contributing to the risk assessment of AMR in the underexplored ocean environment. As antibiotic resistance in marine microorganisms is significantly affected by the concentration of antibiotics in coastal environments, we encourage more studies concentrating on both the phenotypic and genotypic antibiotic resistance of marine archaea. This may facilitate a comprehensive evaluation of the capacity of marine microorganisms to spread AMR and the implementation of suitable control measures to protect environmental safety and human health.

The changing nature of groundwater in the global water cycle.

In recent decades, climate change and other anthropogenic activities have substantially affected groundwater systems worldwide. These impacts include changes in groundwater recharge, discharge, flow, storage, and distribution. Climate-induced shifts are evident in altered recharge rates, greater groundwater contribution to streamflow in glacierized catchments, and enhanced groundwater flow in permafrost areas. Direct anthropogenic changes include groundwater withdrawal and injection, regional flow regime modification, water table and storage alterations, and redistribution of embedded groundwater in foods globally. Notably, groundwater extraction contributes to sea level rise, increasing the risk of groundwater inundation in coastal areas. The role of groundwater in the global water cycle is becoming more dynamic and complex. Quantifying these changes is essential to ensure sustainable supply of fresh groundwater resources for people and ecosystems.

Maternal or Paternal Antibiotics? Intergenerational Transmission and Reproductive Toxicity in Zebrafish.

Despite the known direct toxicity of various antibiotics to aquatic organisms, the potential chronic impact through intergenerational transmission on reproduction remains elusive. Here, we exposed zebrafish to a mixture of 15 commonly consumed antibiotics at environmentally relevant concentrations (1 and 100 µg L-1) with a cross-mating design. A high accumulation of antibiotics was detected in the ovary (up to 904.58 ng g-1) and testis (up to 1704.49 ng g-1) of F0 fish. The transmission of antibiotics from the F0 generation to the subsequent generation (F1 offspring) was confirmed with a transmission rate (ki) ranging from 0.11 to 2.32. The maternal transfer of antibiotics was significantly higher, relative to paternal transfer, due to a greater role of transmission through ovarian enrichment and oviposition compared to testis enrichment. There were similar impairments in reproductive and developmental indexes on F1 eggs found following both female and male parental exposure. Almost all antibiotics were eliminated in F2 eggs in comparison to F1 eggs. However, there were still reproductive and developmental toxic responses observed in F2 fish, suggesting that antibiotic concentration levels were not the only criterion for evaluating the toxic effects for each generation. These findings unveil the intergenerational transmission mechanism of antibiotics in fish models and underscore their potential and lasting impact in aquatic environments.

Uncovering the processes of microbial community assembly in the near-surface sediments of a climate-sensitive glacier-fed lake.

Glacier-fed lakes are characterized by cold temperatures, high altitudes, and nutrient-poor conditions. Despite these challenging conditions, near-surface sediments of glacier-fed lakes harbor rich microbial communities that are critical for ecosystem functioning and serve as a bridge between aquatic ecology and the deep subsurface biosphere. However, there is limited knowledge regarding the microbial communities and their assembly processes in these sediments, which are highly vulnerable to climate change. To fill this knowledge gap, this study systematically analyzed environmental variables, microbial communities, diversity, co-occurrence relationships, and community assembly processes in the near-surface sediments of a glacier-fed lake in the Tibetan Plateau. The results revealed distinct vertical gradients in microbial diversity and subcommunities, highlighting the significant influence of selection processes and adaptive abilities on microbial communities. Specifically, specialists played a crucial role within the overall microbial communities. Microbial assembly was primarily driven by homogeneous selection, but its influence declined with increasing depth. In contrast, homogenizing dispersal showed an opposite pattern, and the bottom layer exhibited heterogeneous selection and undominated processes. These patterns of microbial assembly were primarily driven by environmental gradients, with significant contributions from processes associated to ammonium and organic matter deposition, as well as chemical precipitation in response to a warming climate. This study enhances our understanding of the microbial communities and assembly processes in the near-surface sediments of glacier-fed lakes and sheds light on geo-microbiological processes in climate-sensitive lacustrine sediments.

A Fractional-order dual-continuum model to capture non-Fickian solute transport in a regional-scale fractured aquifer.

Contaminant transport in fractured media exhibits complex dynamics, including multiple peaks in breakthrough curves (BTCs) and non-Fickian diffusion, thereby posing significant challenges to the application of traditional transport models. Here we undertook a detailed study of a natural-gradient tracer test conducted in a regional-scale fractured carbonate aquifer situated in southwestern Germany, where the observed BTCs contained both dual peaks and positive skewness. These BTCs were used to optimize parameters and interpret their physical meanings for several transport models, including the dual-continuum model (DCM) and the fractional derivative equation (FDE) model. Tracer concentration distributions were simulated in both single- and dual-continuum media employing the DCM and FDE models. Our results demonstrated that while the DCM model could reasonably replicate the bimodal BTC, the FDE (which accounts for solute retention) outperformed in capturing the heavy-tailed BTC. This was attributed to the limitations of grid-based numerical models that assume Fickian diffusion and fail to map small-scale medium heterogeneity exhaustively. In contrast, a parsimonious model like the FDE, with upscaled parameters, was found to be more effective in capturing regional-scale non-Fickian transport. To further characterize the multiple BTC peaks the standard FDE missed, we proposed a fractional derivative dual-continuum model (fDCM). This model was found to be adept at capturing both the multi-peak and late-time heavy tail in the BTC. Our study thus opens an alternate pathway for modeling solute transport in regional-scale fractured to partially karstified aquifers.

Poly- and Perfluoroalkyl Substances Induce Immunotoxicity via the TLR Pathway in Zebrafish: Links to Carbon Chain Length.

Previous studies have reported the immunotoxicity of per- and polyfluoroalkyl substances (PFASs), but it remains a significant challenge to assess over 10,000 distinct PFASs registered in the distributed structure-searchable toxicity (DSSTox) database. We aim to reveal the mechanisms of immunotoxicity of different PFASs and hypothesize that PFAS immunotoxicity is dependent on the carbon chain length. Perfluorobutanesulfonic acid (PFBA), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) representing different carbon chain lengths (4-9) at environmentally relevant levels strongly reduced the host's antibacterial ability during the zebrafish's early-life stage. Innate and adaptive immunities were both suppressed after PFAS exposures, exhibiting a significant induction of macrophages and neutrophils and expression of immune-related genes and indicators. Interestingly, the PFAS-induced immunotoxic responses were positively correlated to the carbon chain length. Moreover, PFASs activated downstream genes of the toll-like receptor (TLR), uncovering a seminal role of TLR in PFAS immunomodulatory effects. Myeloid differentiation factor 88 (MyD88) morpholino knock-down experiments and MyD88 inhibitors alleviated the immunotoxicity of PFASs. Overall, the comparative results demonstrate differences in the immunotoxic responses of PFASs due to carbon chain length in zebrafish, providing new insights into the prediction and classification of PFASs mode of toxic action based on carbon chain length.

Evaluating the spatial and temporal distribution of emerging contaminants in the Pearl River Basin for regulating purposes.

Little information is available on how the types, concentrations, and distribution of chemicals have evolved over the years. The objective of the present study is therefore to review the spatial and temporal distribution profile of emerging contaminants with limited toxicology data in the pearl river basin over the years to build up the emerging contaminants database in this region for risk assessment and regulatory purposes. The result revealed that seven groups of emerging contaminants were abundant in this region, and many emerging contaminants had been detected at much higher concentrations before 2011. Specifically, antibiotics, phenolic compounds, and acidic pharmaceuticals were the most abundant emerging contaminants detected in the aquatic compartment, while phenolic compounds were of the most profound concern in soil. Flame retardants and plastics were the most frequently studied chemicals in organisms. The abundance of the field concentrations and frequencies varied considerably over the years, and currently available data can hardly be used for regulation purposes. It is suggested that watershed management should establish a regular monitoring scheme and comprehensive database to monitor the distribution of emerging contaminants considering the highly condensed population in this region. The priority monitoring list should be formed in consideration of historical abundance, potential toxic effects of emerging contaminants as well as the distribution of heavily polluting industries in the region.

Coastal phytoplankton blooms expand and intensify in the 21st century.

Phytoplankton blooms in coastal oceans can be beneficial to coastal fisheries production and ecosystem function, but can also cause major environmental problems1,2-yet detailed characterizations of bloom incidence and distribution are not available worldwide. Here we map daily marine coastal algal blooms between 2003 and 2020 using global satellite observations at 1-km spatial resolution. We found that algal blooms occurred in 126 out of the 153 coastal countries examined. Globally, the spatial extent (+13.2%) and frequency (+59.2%) of blooms increased significantly (P < 0.05) over the study period, whereas blooms weakened in tropical and subtropical areas of the Northern Hemisphere. We documented the relationship between the bloom trends and ocean circulation, and identified the stimulatory effects of recent increases in sea surface temperature. Our compilation of daily mapped coastal phytoplankton blooms provides the basis for global assessments of bloom risks and benefits, and for the formulation or evaluation of management or policy actions.

Groundwater Quality and Health: Making the Invisible Visible.

Linking groundwater quality to health will make the invisible groundwater visible, but there are knowledge gaps to understand the linkage which requires cross-disciplinary convergent research. The substances in groundwater that are critical to health can be classified into five types according to the sources and characteristics: geogenic substances, biogenic elements, anthropogenic contaminants, emerging contaminants, and pathogens. The most intriguing questions are related to quantitative assessment of human health and ecological risks of exposure to the critical substances via natural or induced artificial groundwater discharge: What is the list of critical substances released from discharging groundwater, and what are the pathways of the receptors' exposure to the critical substances? How to quantify the flux of critical substances during groundwater discharge? What procedures can we follow to assess human health and ecological risks of groundwater discharge? Answering these questions is fundamental for humans to deal with the challenges of water security and health risks related to groundwater quality. This perspective provides recent progresses, knowledge gaps, and future trends in understanding the linkage between groundwater quality and health.

Coastal aquaculture regulates phosphorus cycling in estuarine wetlands: Mobilization, kinetic resupply, and source-sink process.

Estuarine mangrove wetlands have gradually declined owing to the growing construction of aquaculture ponds. How the speciation, transition, and migration of phosphorus (P) adaptively change in the sediments of this pond-wetland ecosystem remains unclear. In this study, we used high-resolution devices to explore the contrasting P behaviors associated with the redox cycles of Fe-Mn-S-As in estuarine and pond sediments. The results showed that the construction of aquaculture ponds increased the content or percentage of the silt, organic carbon, and P fractions in sediments. Dissolved organic P (DOP) concentrations in pore water were fluctuant with depths, accounting for only 18±15% and 20±11% of total dissolved P (TDP) in estuarine and pond sediment, respectively. Furthermore, DOP was less strongly correlated with other P species, including Fe, Mn, and sulfide. The coupling of dissolved reactive P (DRP) and TDP with Fe and sulfide confirmed that P mobility is regulated by Fe redox cycling in estuarine sediments, whereas Fe(III) reduction and sulfate reduction co-regulate P remobilization in pond sediments. The apparent diffusion flux revealed all sediments acting as sources for TDP (0.04-0.1 mg m-2 d-1) to the overlying water, while mangrove sediments were sources of DOP, and pond sediments were major sources of DRP. The DIFS model overestimated the P kinetic resupply ability, which was evaluated using DRP rather than TDP. This study improves our understanding of P cycling and budget in aquaculture pond-mangrove ecosystems and has important implications for understanding water eutrophication more effectively.

Integrated effects of bioturbation, warming and sea-level rise on mobility of sulfide and metalloids in sediment porewater of mangrove wetlands.

Global warming and sea-level rise exert profound impacts on coastal mangrove ecosystems, where widespread benthic crabs change sediment properties and regulate material cycles. How crab bioturbation perturbs the mobilities of bioavailable arsenic (As), antimony (Sb) and sulfide in sediment-water systems and their variability in response to temperature and sea-level rise is still unknown. By combining field monitoring and laboratory experiments, we found that As was mobilized under sulfidic conditions while Sb was mobilized under oxic conditions in mangrove sediments. Crab burrowing greatly enhanced oxidizing conditions, resulting in enhanced Sb mobilization and release but As sequestration by iron/manganese oxides. In control experiments with non-bioturbation, the more sulfidic conditions triggered the contrasting situation of As remobilization and release but Sb precipitation and burial. Moreover, the bioturbated sediments were highly heterogeneous for spatial distributions of labile sulfide, As and Sb as presented by 2-D high-resolution imaging and Moran's Index (patchy at the <1 cm scale). Warming stimulated stronger burrowing activities, which led to more oxic conditions and further Sb mobilization and As sequestration, whilst sea-level rise did the opposite via suppressing crab burrowing activity. This work highlights that global climate changes have the potential to significantly alter element cycles in coastal mangrove wetlands by regulating benthic bioturbation and redox chemistry.

A data-driven approach to exploring the causal relationships between distributed pumping activities and aquifer drawdown.

Groundwater depletion, typically caused by the distributed pumping activities of multiple stakeholders (i.e., water users) that share a hydrologically connected aquifer, has led to severe environmental and ecological problems in many river basins worldwide. Conventionally, the effects of pumping on aquifer depletion are quantified using well hydraulics or physically based hydrological models in groundwater management. However, the derivation of well hydraulics-based analytical solutions requires numerous simplifying assumptions, while the construction and calibration of a physically based groundwater flow model require detailed information about the subsurface properties, which are subject to large uncertainties. In this study, we develop a novel modeling framework that does not rely on well hydraulics or groundwater flow models. The proposed framework integrates (1) a deep learning model that captures the spatiotemporal variations in the aquifer in response to distributed pumping activities in multiple well fields and (2) a statistical causal inference model that identifies the causal networks among stakeholders to quantify the causal effects of individual pumping activities on aquifer depletion. The proposed framework is tested on a synthetic case study site with well fields that have various spatial distributions and pumping rates. The modeling results show that the deep learning method can effectively capture the water table dynamics influenced by distributed pumping activities with R2 >90 % for all observation data. More importantly, our model is capable of assessing the causal networks between the drawdown of water table and the pumping activities of multiple well fields and quantifying their causal strengths. These results suggest that our modeling framework can be used to explicitly assess the extent to which each individual stakeholder's pumping activities contribute to aquifer depletion at the system level. The concepts and techniques developed in this study can be used to resolve classic externality problems in the context of common-pool groundwater management.

Vertical Hydrologic Exchange Flows Control Methane Emissions from Riverbed Sediments.

CH4 emissions from inland waters are highly uncertain in the current global CH4 budget, especially for streams, rivers, and other lotic systems. Previous studies have attributed the strong spatiotemporal heterogeneity of riverine CH4 to environmental factors such as sediment type, water level, temperature, or particulate organic carbon abundance through correlation analysis. However, a mechanistic understanding of the basis for such heterogeneity is lacking. Here, we combine sediment CH4 data from the Hanford reach of the Columbia River with a biogeochemical-transport model to show that vertical hydrologic exchange flows (VHEFs), driven by the difference between river stage and groundwater level, determine CH4 flux at the sediment-water interface. CH4 fluxes show a nonlinear relationship with the magnitude of VHEFs, where high VHEFs introduce O2 into riverbed sediments, which inhibit CH4 production and induce CH4 oxidation, and low VHEFs cause transient reduction in CH4 flux (relative to production) due to reduced advective CH4 transport. In addition, VHEFs lead to the hysteresis of temperature rise and CH4 emissions because high river discharge caused by snowmelt in spring leads to strong downwelling flow that offsets increasing CH4 production with temperature rise. Our findings reveal how the interplay between in-stream hydrologic flux besides fluvial-wetland connectivity and microbial metabolic pathways that compete with methanogenic pathways can produce complex patterns in CH4 production and emission in riverbed alluvial sediments.

Perfluorononanoic Acid Induces Neurotoxicity via Synaptogenesis Signaling in Zebrafish.

Perfluorononanoic acid (PFNA), commonly used as an alternative polyfluorinated compound (PFC) of perfluorooctanoic acid (PFOA), has been widely detected in the aquatic environment. Previous ecotoxicological and epidemiological results suggested that some neurobehavioral effects were associated with PFC exposure; however, the ecological impacts and underlying neurotoxicity mechanisms remain unclear, particularly in aquatic organisms during sensitive, early developmental stages. In this study, zebrafish embryos were exposed to environmentally relevant concentrations of PFNA for 120 h, and the neurological effects of PFNA were comprehensively assessed using transcriptional, biochemical, morphological, and behavioral assays. RNA sequencing and advanced bioinformatics analyses predicted and characterized the key biological processes and pathways affected by PFNA exposure, which included the synaptogenesis signaling pathway, neurotransmitter synapse, and CREB signaling in neurons. Neurotransmitter levels (acetylcholine, glutamate, 5-hydroxytryptamine, γ-aminobutyric acid, dopamine, and noradrenaline) were significantly decreased in zebrafish larvae, and the Tg(gad67:GFP) transgenic line revealed a decreased number of GABAergic neurons in PFNA-treated larvae. Moreover, the swimming distance, rotation frequency, and activity degree were also significantly affected by PFNA, linking molecular-level changes to behavioral consequences.

Sunlight-mediated CaO2 inactivation of pathogen indicator organisms in surface water system: Roles of reactive species, characterization of pathogen inactivation.

In the era of the current epidemic, it is urgent to control pathogens in sewage, eliminate the source of infection, and optimize the technology for killing pathogens. Combining calcium peroxide (CaO2) with sunlight is considered a potentially efficient, economical, and eco-friendly method for pathogen-contaminated water remediation. This paper evaluated the solar activating properties of CaO2 for inactivating pathogenic indicators and explored the roles of reactive species contributing to pathogen inactivation. Moreover, these reactive species' average steady-state concentrations and second-order reaction rate were tentatively explored, and mechanistic model for photoinactivation were establishment. Pathogen's inactivation was mainly attributed to direct photoinactivation (13∼50%) and exogenous indirect mechanisms with corresponding contributions of reactive species, i.e., OH- (14∼23%), 1O2 (12∼28%), •OH (20∼32%), O2•- (12∼16%), and H2O2 (6∼11%). Furthermore, cell membrane rupture and DNA damage were observed by transmission electron microscopy (TEM) and agarose gel electrophoresis (AGE) experiments. Among experiments on common aqueous constituents influencing photoinactivation, copper and iron ions were found to promote a pathogen-inactivating ability of the system, while fulvic acids (FA) and humic acid (HA) had the opposite effect. This study revealed the potential of CaO2/sunlight to inactivate pathogens and laid a foundation for its application in inactivating pathogens in surface water.

Deficiency and excess of groundwater iodine and their health associations.

More than two billion people worldwide have suffered thyroid disorders from either iodine deficiency or excess. By creating the national map of groundwater iodine throughout China, we reveal the spatial responses of diverse health risks to iodine in continental groundwater. Greater non-carcinogenic risks relevant to lower iodine more likely occur in the areas of higher altitude, while those associated with high groundwater iodine are concentrated in the areas suffered from transgressions enhanced by land over-use and intensive anthropogenic overexploitation. The potential roles of groundwater iodine species are also explored: iodide might be associated with subclinical hypothyroidism particularly in higher iodine regions, whereas iodate impacts on thyroid risks in presence of universal salt iodization exhibit high uncertainties in lower iodine regions. This implies that accurate iodine supply depending on spatial heterogeneity and dietary iodine structure optimization are highly needed to mitigate thyroid risks in iodine-deficient and -excess areas globally.