Association of Urinary Metals With Cardiovascular Disease Incidence and All-Cause Mortality in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Exposure to metals has been associated with cardiovascular disease (CVD) end points and mortality, yet prospective evidence is limited beyond arsenic, cadmium, and lead. In this study, we assessed the prospective association of urinary metals with incident CVD and all-cause mortality in a racially diverse population of US adults from MESA (the Multi-Ethnic Study of Atherosclerosis). METHODS: We included 6599 participants (mean [SD] age, 62.1 [10.2] years; 53% female) with urinary metals available at baseline (2000 to 2001) and followed through December 2019. We used Cox proportional hazards models to estimate the adjusted hazard ratio and 95% CI of CVD and all-cause mortality by baseline urinary levels of cadmium, tungsten, and uranium (nonessential metals), and cobalt, copper, and zinc (essential metals). The joint association of the 6 metals as a mixture and the corresponding 10-year survival probability was calculated using Cox Elastic-Net. RESULTS: During follow-up, 1162 participants developed CVD, and 1844 participants died. In models adjusted by behavioral and clinical indicators, the hazard ratios (95% CI) for incident CVD and all-cause mortality comparing the highest with the lowest quartile were, respectively: 1.25 (1.03, 1.53) and 1.68 (1.43, 1.96) for cadmium; 1.20 (1.01, 1.42) and 1.16 (1.01, 1.33) for tungsten; 1.32 (1.08, 1.62) and 1.32 (1.12, 1.56) for uranium; 1.24 (1.03, 1.48) and 1.37 (1.19, 1.58) for cobalt; 1.42 (1.18, 1.70) and 1.50 (1.29, 1.74) for copper; and 1.21 (1.01, 1.45) and 1.38 (1.20, 1.59) for zinc. A positive linear dose-response was identified for cadmium and copper with both end points. The adjusted hazard ratios (95% CI) for an interquartile range (IQR) increase in the mixture of these 6 urinary metals and the corresponding 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56) and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91) and -2.0% (-2.6, -1.5) for all-cause mortality. CONCLUSIONS: This epidemiological study in US adults indicates that urinary metal levels are associated with increased CVD risk and mortality. These findings can inform the development of novel preventive strategies to improve cardiovascular health.

Arsenic Exposure, Blood DNA Methylation, and Cardiovascular Disease.

BACKGROUND: Epigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD. METHODS: Blood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis. RESULTS: A total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic. CONCLUSIONS: Differential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

Arsenic speciation analysis in human urine for long term epidemiological studies: The Multi-Ethnic Study of Atherosclerosis (MESA).

Arsenic is a ubiquitous toxic metalloid causing serious health problems. Speciation analysis of arsenic in human urine provides valuable insights for large-scale epidemiological studies and informs on sources of exposure as well as human metabolism. The Multi-Ethnic Study of Atherosclerosis (MESA) is a valuable cohort for assessing chronic low-moderate arsenic exposure and health effects in an ethnically diverse US population. We present a state-of-the-art arsenic speciation analysis methodology and its application to 7677 MESA spot urine samples based on high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. This method is fast, robust and detects a total of 11 individual As species at method detection limits of 0.02-0.03 µg arsenic/L urine for each individual species. Our analytical approach features excellent mean method accuracy (98%) and precision (5%) for the main arsenic species in urine (arsenobetaine, methylarsonic acid, dimethylarsinic acid, and total inorganic As); intra- (3-6%) and inter-day coefficients of variability (5-6%); column recovery (96 ± 7%); and spike recovery (97 ± 6%). The main arsenic species were detectable in ≥95% of urine samples due to the implementation of an oxidation step. Each individual minor arsenic species was detectable in ≤25% of all urines, although at least one of them was detected in almost half the participants. We identified two minor urinary arsenic species as dimethylarsinoylacetic acid and dimethylarsinoylpropionic acid, potential metabolites of seafood-related arsenicals. We observed differences in individual As species excretion by race/ethnicity, with Asian-American participants featuring 3-4 times higher concentrations compared to other participants. We also found differences by site, body mass index, smoking status, rice intake, and water arsenic levels, potentially indicating different exposures or related to individual bio-metabolism. The proposed approach is suitable for epidemiological studies and the collected data will constitute the base for future research on potential health effects of chronic low-level arsenic exposure.

Urinary concentrations of metals before and after volcanic eruption: a natural experiment surrounding the eruption of Volcán de Fuego, 2018.

Volcanic eruptions increase environmental heavy metal concentrations, yet little research has been performed on their extrapulmonary human health effects. We fortuitously collected biological samples in a cohort of Guatemalan sugarcane cutters in the area surrounding Volcán de Fuego before and after the June 2018 eruption. We sought to determine whether stratovolcanic activity was associated with changes in urinary concentrations of heavy metals in a cohort of sugarcane workers. In this exploratory analysis, we found significant increases in urinary arsenic, (ß = 1.46, P < 0.0001), cadmium (ß = 1.03, P < 0.0001), and lead (ß = 0.87, P = 0.003) in participants with residential proximity to Volcán de Fuego as compared to participants farther away, suggesting that volcanic activity could be associated with acute heavy metal exposures. This natural experiment is, to our knowledge, the first of its kind and suggests a need for more research into heavy metal exposure-related health impacts of volcanic eruptions.

Metal distribution, bioavailability and isotope variations in polluted soils from Lower Swansea Valley, UK.

Soils in the Lower Swansea Valley, (United Kingdom) contain elevated level of metals, enough to cause direct or indirect effects on human health. This study assesses the severity of soil pollution and bioavailability of Cu and other metals (Ni, Zn, Co, Pb and Cr) in soils with various distances from a Ni refinery. We compare Cu concentrations in operationally defined soil fractions (bioavailable, bound to Fe/Mn oxide and incorporated in organic matter) with other metals (Ni, Zn, Pb, Co, Cr) usually occurring in ores used in metallurgic processes and report their pollution and geoaccumulation indices (PI and Igeo). Further, we use Cu stable isotope ratios (δ65Cu) to trace the fate and mobility of Cu in soils. Our data suggest a point source of contamination for some of the heavy metals including Ni (Igeo = 1.9), Zn (Igeo = 0.28) and Cu (Igeo = 3.6) near the Ni refinery. However, Co (Igeo = 0.15) and Pb (Igeo = 3.3) contaminations are likely to be linked to different sources. No elevated Cr levels (Igeo= -0.07) occur in any of the studied soils. All soil metals are predominantly associated with organic matter (>50%) which  reduces their bioavailibility and thus their risk for ecological and human health. The Cu isotope data show that Cu in soil organic matter is enriched in 65Cu, while the lighter isotopes (63Cu) remain in the dissolved bioavailable Cu fraction (Δ65Cuorganic-bioavailable is +0.12 ± 0.13‰). This suggests the preferential complexation of 65Cu with soil organic matter after dissolution of Cu deposited to the soil. Thus, Cu isotope data can effectively indicate pathways of metal migration in polluted soils.

Se Isotopes as Groundwater Redox Indicators: Detecting Natural Attenuation of Se at an in Situ Recovery U Mine.

One of the major ecological concerns associated with the in situ recovery (ISR) of uranium (U) is the environmental release of soluble, toxic selenium (Se) oxyanions generated by mining. Post-mining natural attenuation by the residual reductants in the ore body and reduced down-gradient sediments should mitigate the risk of Se contamination in groundwater. In this work, we investigate the Se concentrations and Se isotope systematics of groundwater and of U ore bearing sediments from an ISR site at Rosita, TX, USA. Our results show that selenate (Se(VI)) is the dominant Se species in Rosita groundwater, and while several up-gradient wells have elevated Se(VI), the majority of the ore zone and down-gradient wells have little or no Se oxyanions. In addition, the δ82SeVI of Rosita groundwater is generally elevated relative to the U ore up to +6.14‰, with the most enriched values observed in the ore-zone wells. Increasing δ82Se with decreasing Se(VI) conforms to a Rayleigh type distillation model with an ε of -2.25‰ ± 0.61‰, suggesting natural Se(VI) reduction occurring along the hydraulic gradient at the Rosita ISR site. Furthermore, our results show that Se isotopes are excellent sensors for detecting and monitoring post-mining natural attenuation of Se oxyanions at ISR sites.

Fate of Selenium in Soils at a Seleniferous Site Recorded by High Precision Se Isotope Measurements.

Selenium poisoning is a significant health problem in parts of Punjab, India, which is an area of intense agricultural productivity. To determine the complex soil dynamics that control distribution of Se in this area, we measured concentrations and δ(82/76)Se of bulk Se and individual Se pools in four soil profiles. This was compared against δ(82/76)Se of crops and groundwater used for irrigation. The isotopic composition of bulk Se and component Se pools reveal spatial heterogeneity. The bulk δ(82/76)Se show progressively lower values with increasing soil depth indicating the preferential migration of isotopically lighter Se downward through the soil profile. The δ(82/76)Se of water-soluble Se is isotopically heavier than δ(82/76)Se of adsorbed Se, suggesting Se isotope fractionation by reduction prior to scavenging by reactive minerals in the soil. The organically bound Se is isotopically lighter than water-soluble Se and correlates with the C/N ratio at different soil depths. Thus, Se immobilization by redox cycling controls the biogeochemical Se cycle in the soil. Se isotope ratios help to trace biochemical processes of Se in agricultural seleniferous soils and provide an important assessment for better soil management mitigating Se concentrations of ecotoxicological levels.

Metal-binding amino acid ligands commonly found in metalloproteins differentially fractionate copper isotopes.

Copper (Cu) is a cofactor in numerous key proteins and, thus, an essential element for life. In biological systems, Cu isotope abundances shift with metabolic and homeostatic state. However, the mechanisms underpinning these isotopic shifts remain poorly understood, hampering use of Cu isotopes as biomarkers. Computational predictions suggest that isotope fractionation occurs when proteins bind Cu, with the magnitude of this effect dependent on the identity and arrangement of the coordinating amino acids. This study sought to constrain equilibrium isotope fractionation values for Cu bound by common amino acids at protein metal-binding sites. Free and bound metal ions were separated via Donnan dialysis using a cation-permeable membrane. Isotope ratios of pre- and post-dialysis solutions were measured by MC-ICP-MS following purification. Sulfur ligands (cysteine) preferentially bound the light isotope (63Cu) relative to water (Δ65Cucomplex-free = - 0.48 ± 0.18‰) while oxygen ligands favored the heavy isotope (65Cu; + 0.26 ± 0.04‰ for glutamate and + 0.16 ± 0.10‰ for aspartate). Binding by nitrogen ligands (histidine) imparted no isotope effect (- 0.01 ± 0.04‰). This experimental work unequivocally demonstrates that amino acids differentially fractionate Cu isotopes and supports the hypothesis that metalloprotein biosynthesis affects the distribution of transition metal isotopes in biological systems.

Analysis of urinary potassium isotopes and association with pancreatic health: healthy, diabetic and cancerous states.

Background: More than 700 million people worldwide suffer from diseases of the pancreas, such as diabetes, pancreatitis and pancreatic cancer. Often dysregulation of potassium (K+) channels, co-transporters and pumps can promote development and progression of many types of these diseases. The role of K+ transport system in pancreatic cell homeostasis and disease development remains largely unexplored. Potassium isotope analysis (δ41K), however, might have the potential to detect minute changes in metabolic processes relevant for pancreatic diseases. Methods: We assessed urinary K isotope composition in a case-control study by measuring K concentrations and δ41K in spot urines collected from patients diagnosed with pancreatic cancer (n=18), other pancreas-related diseases (n=14) and compared those data to healthy controls (n=16). Results: Our results show that urinary K+ levels for patients with diseased pancreas (benign and pancreatic cancer) are significantly lower than the healthy controls. For δ41K, the values tend to be higher for individuals with pancreatic cancer (mean δ41K = -0.58 ± 0.33‰) than for healthy individuals (mean δ41K = -0.78 ± 0.19‰) but the difference is not significant (p=0.08). For diabetics, urinary K+ levels are significantly lower (p=0.03) and δ41K is significantly higher (p=0.009) than for the healthy controls. These results suggest that urinary K+ levels and K isotopes can help identify K disturbances related to diabetes, an associated factors of all-cause mortality for diabetics. Conclusion: Although the K isotope results should be considered exploratory and hypothesis-generating and future studies should focus on larger sample size and δ41K analysis of other K-disrupting diseases (e.g., chronic kidney disease), our data hold great promise for K isotopes as disease marker.

Tampons as a source of exposure to metal(loid)s.

BACKGROUND: Between 52-86% of people who menstruate in the United States use tampons-cotton and/or rayon/viscose 'plugs'-to absorb menstrual blood in the vagina. Tampons may contain metals from agricultural or manufacturing processes, which could be absorbed by the vagina's highly absorptive tissue, resulting in systemic exposure. To our knowledge, no previous studies have measured metals in tampons. OBJECTIVES: We evaluated the concentrations of 16 metal(loid)s in 30 tampons from 14 tampon brands and 18 product lines and compared the concentrations by tampon characteristics. METHODS: About 0.2 - 0.3 g from each tampon (n = 60 samples) were microwave-acid digested and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) to determine concentrations of arsenic, barium, calcium, cadmium, cobalt, chromium, copper, iron, manganese, mercury, nickel, lead, selenium, strontium, vanadium, and zinc. We compared concentrations by several tampon characteristics (region of purchase, organic material, brand type) using median quantile mixed models. RESULTS: We found measurable concentrations of all 16 metals assessed. We detected concentrations of several toxic metals, including elevated mean concentrations of lead (geometric mean [GM] = 120 ng/g), cadmium (GM = 6.74 ng/g), and arsenic (GM = 2.56 ng/g). Metal concentrations differed by region of tampon purchase (US versus European Union/United Kingdom), by organic versus non-organic material, and for store- versus name-brand tampons. Most metals differed by organic status; lead concentrations were higher in non-organic tampons while arsenic was higher in organic tampons. No categoriy had consistently lower concentrations of all or most metals. DISCUSSION: Tampon use is a potential source of metal exposure. We detected all 16 metals in at least one sampled tampon, including some toxic metals like lead that has no "safe" exposure level. Future research is needed to replicate our findings and determine whether metals can leach out of tampons and cross the vaginal epithelium into systemic circulation.

An epigenome-wide study of selenium status and DNA methylation in the Strong Heart Study.

BACKGROUND: Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. METHODS: Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. RESULTS: The mean (standard deviation) urinary Se concentration was 51.8 (25.1) µg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [MAP4K2], cg11270656 [GPIHBP1]) identified in linear regressions. CONCLUSIONS: Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints.

Method validation for (ultra)-trace element concentrations in urine for small sample volumes in large epidemiological studies: application to the population-based epidemiological multi-ethnic study of atherosclerosis (MESA).

Analysis of essential and non-essential trace elements in urine has emerged as a valuable tool for assessing occupational and environmental exposures, diagnosing nutritional status and guiding public health and health care intervention. Our study focused on the analysis of trace elements in urine samples from the Multi-Ethnic Study of Atherosclerosis (MESA), a precious resource for health research with limited sample volumes. Here we provide a comprehensive and sensitive method for the analysis of 18 elements using only 100 µL of urine. Method sensitivity, accuracy, and precision were assessed. The analysis by inductively coupled plasma mass spectrometry (ICP-MS) included the measurement of antimony (Sb), arsenic (As), barium (Ba), cadmium (Cd), cesium (Cs), cobalt (Co), copper (Cu), gadolinium (Gd), lead (Pb), manganese (Mn), molybdenum (Mo), nickel (Ni), selenium (Se), strontium (Sr), thallium (Tl), tungsten (W), uranium (U), and zinc (Zn). Further, we reported urinary trace element concentrations by covariates including gender, ethnicity/race, smoking and location. The results showed good accuracy and sensitivity of the ICP-MS method with the limit of detections rangings between 0.001 µg L-1 for U to 6.2 µg L-1 for Zn. Intra-day precision for MESA urine analysis varied between 1.4% for Mo and 26% for Mn (average 6.4% for all elements). The average inter-day precision for most elements was <8.5% except for Gd (20%), U (16%) and Mn (19%) due to very low urinary concentrations. Urinary mean concentrations of non-essential elements followed the order of Sr > As > Cs > Ni > Ba > Pb > Cd > Gd > Tl > W > U. The order of urinary mean concentrations for essential trace elements was Zn > Se > Mo > Cu > Co > Mn. Non-adjusted mean concentration of non-essential trace elements in urine from MESA participants follow the order Sr > As > Cs > Ni > Ba > Pb > Cd > Gd > Tl > W > U. The unadjusted urinary mean concentrations of essential trace elements decrease from Zn > Se > Mo > Cu > Co > Mn.

Contribution of arsenic and uranium in private wells and community water systems to urinary biomarkers in US adults: The Strong Heart Study and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Chronic exposure to inorganic arsenic (As) and uranium (U) in the United States (US) occurs from unregulated private wells and federally regulated community water systems (CWSs). The contribution of water to total exposure is assumed to be low when water As and U concentrations are low. OBJECTIVE: We examined the contribution of water As and U to urinary biomarkers in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially/ethnically diverse urban U.S. communities. METHODS: We assigned residential zip code-level estimates in CWSs (µg/L) and private wells (90th percentile probability of As >10 µg/L) to up to 1485 and 6722 participants with dietary information and urinary biomarkers in the SHFS (2001-2003) and MESA (2000-2002; 2010-2011), respectively. Urine As was estimated as the sum of inorganic and methylated species, and urine U was total uranium. We used linear mixed-effects models to account for participant clustering and removed the effect of dietary sources via regression adjustment. RESULTS: The median (interquartile range) urine As was 5.32 (3.29, 8.53) and 6.32 (3.34, 12.48) µg/L for SHFS and MESA, respectively, and urine U was 0.037 (0.014, 0.071) and 0.007 (0.003, 0.018) µg/L. In a meta-analysis across both studies, urine As was 11% (95% CI: 3, 20%) higher and urine U was 35% (5, 73%) higher per twofold higher CWS As and U, respectively. In the SHFS, zip-code level factors such as private well and CWS As contributed 46% of variation in urine As, while in MESA, zip-code level factors, e.g., CWS As and U, contribute 30 and 49% of variation in urine As and U, respectively. IMPACT STATEMENT: We found that water from unregulated private wells and regulated CWSs is a major contributor to urinary As and U (an estimated measure of internal dose) in both rural, American Indian populations and urban, racially/ethnically diverse populations nationwide, even at levels below the current regulatory standard. Our findings indicate that additional drinking water interventions, regulations, and policies can have a major impact on reducing total exposures to As and U, which are linked to adverse health effects even at low levels.

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Exposure to metals, a newly recognized risk factor for cardiovascular disease (CVD), could be related to atherosclerosis progression. OBJECTIVES: The authors hypothesized that higher urinary levels of nonessential (cadmium, tungsten, uranium) and essential (cobalt, copper, zinc) metals previously associated with CVD would be associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of CVD in MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: We analyzed data from 6,418 MESA participants with spot urinary metal levels at baseline (2000-2002) and 1 to 4 repeated, continuous measures of CAC over a 10-year period. We used linear mixed-effect models to assess the association of baseline urinary metal levels with baseline CAC and cumulative change in CAC over a 10-year period. Urinary metals (µg/g creatinine) and CAC were log transformed. Models were adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. RESULTS: At baseline, the median CAC was 6.3 (Q1-Q3: 0.7-58.2). Comparing the highest to lowest quartile of urinary cadmium, CAC levels were 51% (95% CI: 32%-74%) higher at baseline and 75% (95% CI: 47%-107%) higher over the 10-year period. For urinary tungsten, uranium, and cobalt, the corresponding CAC levels over the 10-year period were 45% (95% CI: 23%-71%), 39% (95% CI: 17%-64%), and 47% (95% CI: 25%-74%) higher, respectively, with no difference for models with and without adjustment for clinical factors. For copper and zinc, the corresponding estimates dropped from 55% to 33% and from 85% to 57%, respectively, after adjustment for clinical factors. The associations of metals with CAC were comparable in magnitude to those for classical CVD risk factors. CONCLUSIONS: Exposure to metals was generally associated with extent of coronary calcification at baseline and follow-up. These findings support that metals are associated with the progression of atherosclerosis, potentially providing a novel strategy for the prevention and treatment of atherosclerosis progression.

Effect of an Arsenic Mitigation Program on Arsenic Exposure in American Indian Communities: A Cluster Randomized Controlled Trial of the Community-Led Strong Heart Water Study Program.

BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM)=13.2 to 7.0µg/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM=14.6 to 6.55µg/g creatinine) and 30% in the Intensive arm (GM=11.2 to 7.82µg/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548.

Endotracheal nebulization of gold nanoparticles for noninvasive pulmonary drug delivery.

Background & aims: Gold nanoparticles (AuNPs) are useful tools for noninvasive drug delivery. AuNP nebulization has shown poor deposition results, and AuNP tracking postadministration has involved methods inapplicable to clinical settings. The authors propose an intratracheal delivery method for minimal AuNP loss and computed tomography scans for noninvasive tracking. Materials & methods: Through high-frequency and directed nebulization postendotracheal intubation, the authors treated rats with AuNPs. Results & conclusion: The study showed a dose-dependent and bilateral distribution of AuNPs causing no short-term distress to the animal or risk of airway inflammation. The study demonstrated that AuNPs do not deposit in abdominal organs and show targeted delivery to human lung fibroblasts, offering a specific and noninvasive strategy for respiratory diseases requiring long-term therapies.

This study presents an alternative method for drug delivery involving gold nanoparticle aerosolization directly into the major airways. Direct nebulization prevents particle loss and avoids drug administration through the blood. The particles can be detected successfully via upper body scans, which are noninvasive and allow for on-demand monitoring. Nanoparticles are flexible tools that can be modified to target specific cells of interest and can be excreted upon completion of their function. These results could represent an alternative method of drug administration in patients needing repeated cytotoxic therapies with known off-target effects.

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis (MESA).

Objective: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD. Methods: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to µg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors. Results: At baseline, the median and interquartile range (25th, 75th) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc. Conclusion: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.

Prevalence of behaviour-related fertility disorders in a clinical sample: results of a pilot study.

INTRODUCTION: There is no doubt that lifestyle factors can be detrimental to fertility. The aim of the present pilot study was to identify initial prevalence rates for behaviour-related fertility disorders in a clinical sample of couples wanting a child. METHODS: Between February 2010 and August 2010, all patients coming for the first time to Heidelberg University's Women's Hospital for consultation on involuntary childlessness were asked to fill out a questionnaire designed by the authors of this article. The questionnaire was based on a review of the relevant literature, with special reference to the latest research findings on behaviour detrimental to fertility. Of the 156 couples addressed, 110 women and 100 men took part in the study. RESULTS: For behaviour-related infertility, 9 % of the women and 3 % of the men in our sample were classified on the basis of BMI <18.5, sexual disorders, or abuse of anabolic steroids. If we include smokers, these figures increase: 11 % female smokers and 18 % male smokers. A further 19 % of the women practised sport to an excessive degree; and 26 % of the women and 53 % of the men had a BMI ≥25. DISCUSSION: The prevalence of behaviour-related fertility disorders should not be underestimated. For the prevention of behaviour-related fertility disorders, it is important to inform the population about lifestyle-mediated fertility risks.

Sociodemographic inequalities in uranium and other metals in community water systems across the USA, 2006-11: a cross-sectional study.

BACKGROUND: The US Environmental Protection Agency (EPA) currently sets maximum contaminant levels (MCLs) for ten metals or metalloids in public drinking water systems. Our objective was to estimate metal concentrations in community water systems (CWSs) across the USA, to establish if sociodemographic or regional inequalities in the metal concentrations exist, and to identify patterns of concentrations for these metals as a mixture. METHODS: We evaluated routine compliance monitoring records for antimony, arsenic, barium, beryllium, cadmium, chromium, mercury, selenium, thallium, and uranium, collected from 2006-11 (2000-11 for uranium; timeframe based on compliance monitoring requirements) by the US EPA in support of their second and third Six-Year Reviews for CWSs. Arsenic, barium, chromium, selenium, and uranium (detectable in >10% records) were included in the main analyses (subgroup and metal mixture analyses; arsenic data reported previously). We compared the mean, 75th percentile, and 95th percentile contaminant concentrations and the percentage of CWSs with concentrations exceeding the MCL across subgroups (region, sociodemographic county-cluster, size of population served, source water type, and CWSs exclusively serving correctional facilities). We evaluated patterns in CWS metal concentration estimate profiles via hierarchical cluster analysis. We created an online interactive map and dashboard of estimated CWS metal concentrations for use in future analyses. FINDINGS: Average metal concentrations were available for a total of 37 915 CWSs across the USA. The total number of monitoring records available was approximately 297 000 for arsenic, 165 000 for barium, 167 000 for chromium, 165 000 for selenium, and 128 000 for uranium. The percentage of analysed CWSs with average concentrations exceeding the MCL was 2·6% for arsenic (MCL=10 µg/L; nationwide mean 1·77 µg/L; n=36 798 CWSs), 2·1% for uranium (MCL=30 µg/L; nationwide mean 4·37 µg/L; n=14 503 CWSs), and less than 0·1% for the other metals. The number of records with detections was highest for uranium (63·1%). 75th and 95th percentile concentrations for uranium, chromium, barium, and selenium were highest for CWSs serving Semi-Urban, Hispanic communities, CWSs reliant on groundwater, and CWSs in the Central Midwest. Hierarchical cluster analysis revealed two distinct clusters: an arsenic-uranium-selenium cluster and a barium-chromium cluster. INTERPRETATIONS: Uranium is an under-recognised contaminant in CWSs. Metal concentrations (including uranium) are elevated in CWSs serving Semi-Urban, Hispanic communities independent of location or region, highlighting environmental justice concerns. FUNDING: US National Institutes of Health Office of the Director, US National Institutes for Environmental Health Sciences, and US National Institute of Dental and Craniofacial Research.