Article

Blood arsenic as a biomarker of arsenic exposure: Results from a prospective study

September 2006
Toxicology 225(2-3):225-33

September 2006
225(2-3):225-33

DOI:10.1016/j.tox.2006.06.010

Source
PubMed

Authors:

Marni Hall

U.S. Food and Drug Administration

Yu Chen

NYU Langone Medical Center

Vesna Slavkovich

Columbia University

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Exposure to arsenic (As)-contaminated drinking water affects millions of people worldwide. Arsenic exposure is associated with skin lesions, skin, lung, kidney and liver cancers, neurologic and cardiovascular effects. Past studies involving biomarkers of As exposure have typically examined urinary As (UAs) (adjusted for urinary creatinine), hair or toenail As, but not blood As (BAs) since blood concentrations are exceedingly low and are not detectable by conventional atomic absorption spectrophotometric techniques. In a case-cohort analysis of 303 newly diagnosed cases of skin lesions, and 849 subcohort members randomly selected from 8092 participants in the health effects of as longitudinal study (HEALS) in Araihazar, Bangladesh, we measured blood, urine and water As concentrations, and examined their associations with each other, and with the risk for skin lesions. BAs concentrations were highly correlated with creatinine-adjusted UAs concentrations (r=0.85) and with water As (WAs) (r=0.75). We observed consistent dose-response relationships between the risk of skin lesions and all the measures of As exposure. Rate ratios (RRs) for skin lesions by quintile of As exposure, adjusted for age and gender, revealed that the two highest quintiles were significantly related to an increased risk of skin lesions for each measure of exposure: BAs, UAs, WAs and a time-weighted water As variable. This prospective study confirms the increased risk of skin lesions in relation to As concentrations in blood, urine and water and also establishes that BAs is a useful biomarker of As exposure in this study population.

Relations between personal exposure to elevated concentrations of arsenic in water and soil and blood arsenic levels amongst people living in rural areas in Limpopo, South Africa

Article

Full-text available

Apr 2023
ENVIRON SCI POLLUT R

Exposure to arsenic even at low levels can lead to adverse health outcomes, however, there is a paucity of research from South Africa in relation to human exposure to arsenic. We investigated long-term exposure of residents in Limpopo province, South Africa, in a cross-sectional study by analysing water, soil and blood arsenic concentrations from two arsenic-exposed (high and medium–low exposure) villages and one non-exposed (control) village. There were statistically significant differences in the distribution of arsenic in water, soil and blood amongst the three sites. The median drinking water arsenic concentration in the high-exposure village was 1.75 µg/L (range = 0.02 to 81.30 µg/L), 0.45 µg/L (range = 0.100 to 6.00 µg/L) in the medium- / low-exposure village and 0.15 µg/L (range = < limit of detection (LOD) to 29.30 µg/L) in the control site. The median soil arsenic concentration in the high-exposure village was 23.91 mg/kg (range = < LOD to 92.10 mg/kg) whilst arsenic concentrations were below the limit of detection in all soil samples collected from the medium-/low-exposure and control villages. In the high-exposure village, the median blood arsenic concentration was 1.6 µg/L (range = 0.7 to 4.2 µg/L); 0.90 µg/L (range = < LOD to 2.5 µg/L) in the medium-/low-exposure village and 0.6 µg/L (range = < LOD to 3.3 µg/L) in the control village. Significant percentages of drinking water, soil and blood samples from the exposed sites were above the internationally recommended guidelines (namely, 10 µg/L, 20 mg/kg and 1 µg/L, respectively). Majority of participants (86%) relied on borehole water for drinking and there was a significant positive correlation between arsenic in blood and borehole water (p-value = 0.031). There was also a statistically significant correlation between arsenic concentrations in participants’ blood and soil samples collected from gardens (p-value = 0.051). Univariate quantile regression found that blood arsenic concentrations increased by 0.034 µg/L (95% CI = 0.02–0.05) for each one unit increase in water arsenic concentrations (p < 0.001). After adjusting for age, water source and homegrown vegetable consumption in multivariate quantile regression, participants from the high-exposure site had significantly higher blood concentrations than those in the control site (coefficient: 1.00; 95% CI = 0.25–1.74; p-value = 0.009) demonstrating that blood arsenic is a good biomarker of arsenic exposure. Our findings also provide new evidence for South Africa on the association between drinking water and arsenic exposure, emphasising the need for the provision of potable water for human consumption in areas with high environmental arsenic concentrations. Supplementary Information The online version contains supplementary material available at 10.1007/s11356-023-26813-9.

What’s in your water? A well-known risk for arsenic toxicity

Article

Full-text available

Apr 2023

Arsenic cannot be tasted, seen or smelled and can vary in concentration between water wells even in condensed areas. American domestic well water is not regulated to meet the same drinking water standards as other types of water supplies and often contains arsenic. If arsenic is not detected in a well water sample, it is unlikely to be found later. Conversely, if it is detected in a new well, it is recommended to retest six months later as levels may fluctuate in the first months following well construction. It is up to the well owner to test their water and remove arsenic through commercially available water filters. If it is not detected and removed via filtration, a variety of serious, yet common, medical conditions may arise from chronic arsenic exposure, some of which are life-threatening. These include diabetes mellitus, hypertension, skin cancer, renal, bladder and lung cancers, polyneuropathy and cardiac QTc prolongation. Testing is best done through urine speciation if an initial total urine arsenic concentration is elevated. Consider a complete blood count, renal and liver function tests, an electrocardiogram as well as a urinalysis assessing for evidence of hematuria when examining patients with histories concerning for chronic arsenic exposure.

Biomonitoring of inorganic arsenic species in pregnancy

Article

Full-text available

Aug 2022

Exposure assessment of inorganic arsenic is challenging due to the existence of multiple species, complexity of arsenic metabolism, and variety of exposure sources. Exposure assessment of arsenic during pregnancy is further complicated by the physiological changes that occur to support fetal growth. Given the well-established toxicity of inorganic arsenic at high concentrations, continued research into the potential health effects of low-level exposure on maternal and fetal health is necessary. Our objectives were to review the value of and challenges inherent in measuring inorganic arsenic species in pregnancy and highlight related research priorities. We discussed how the physiological changes of pregnancy influence arsenic metabolism and necessitate the need for pregnancy-specific data. We reviewed the biomonitoring challenges according to common and novel biological matrices and discussed how each matrix differs according to half-life, bioavailability, availability of laboratory methods, and interpretation within pregnancy. Exposure assessment in both established and novel matrices that accounts for the physiological changes of pregnancy and complexity of speciation is a research priority. Standardization of laboratory method for novel matrices will help address these data gaps. Research is particularly lacking in contemporary populations of pregnant women without naturally elevated arsenic drinking water concentrations (i.e. <10 µg/l).

Nickel (Ni) may have influenced on the MMA(V) reductase and DMA(V) reductase activities for the inorg-As biotransformation process in humans.

Article

Full-text available

Oct 2021

Uttam Chowdhury

Trace elements (As, Se, Zn, Co, Cu, Pb, Cd, Ni, Mn, and Hg) were analyzed in blood of arsenic exposed people in Mexico by using ICP-MS to know the influence of trace elements on the MMA(V) and DMA(V) reductase activities for inorganic arsenic biotransformation process. The correlations between MMA(V) reductase and DMA(V) reductase activities in blood of both females and males were very weak (F, r= +0.06 and M, r= -0.03, respectively). The activities of MMA(V) and DMA(V) reductase were also not depended on ages of those population (r= -0.05 and r= -0.11, respectively). In this study, there were no significant differences of the MMA(V) reductase and DMA(V) reductase activities in bloods of females and males. Nickel concentrations in blood were positively and negatively correlated with MMA(V) and DMA(V) reductase activities in blood of both females and males, respectively. These correlations were statistically significant for females. In conclusion of this study suggest that Ni may have influenced for biotransformation process of inorganic arsenic (inorg-As) in humans and it could enhance arsenic methylation, decrease urinary MMA, and increase urinary DMA. Abbreviation: SAM, S-adenosyl-L-methionine; SAHC, S-adenosyl-L-homocysteine

Association of total arsenic exposure with allostatic load and cardiovascular disease risk

Preprint

Jun 2024

This study aimed to investigate the relationship between arsenic exposure (as measured in urine) and both allostatic load and cardiovascular disease (CVD) risk markers within a representative group of participants from the U.S. noninstitutionalized civilian population. The results revealed individuals with high arsenic levels were significantly older than those with lower arsenic levels. Other findings indicated no significant associations between cardiovascular variables by degree of arsenic exposure as measured by total urinary arsenic. These results underscore the need to assess numerous biomarkers when examining the potential health implications of exposure to arsenic as markers of longer-term Arsenic exposure or consideration of specificity of arsenic species may have yielded different results.

Maternal Blood Levels of Toxic and Essential Elements and Birth Outcomes in Argentina: The EMASAR Study

Article

Full-text available

Mar 2022
Int J Environ Res Publ Health

Pregnant women’s levels of toxic and essential minerals have been linked to birth outcomes yet have not been adequately investigated in South America. In Argentina, n = 696 maternal whole blood samples from Ushuaia (n = 198) and Salta (n = 498) were collected in 2011–2012 among singleton women at 36 ± 12 h postpartum and analyzed for blood concentrations of arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb), copper (Cu), manganese (Mn), selenium (Se) and zinc (Zn). This study examined the associations between maternal elements levels and birth outcomes, and sociodemographic factors contributing to elements levels. Maternal age, parity, body mass index, smoking, and education were linked to concentrations of some but not all elements. In adjusted models, one ln-unit increase in Pb levels was associated with increased gestational age (0.2 weeks, 95% CI = 0.01–0.48) and decreased birth weight (−88.90 g, 95% CI = −173.69 to −4.11) and birth length (−0.46 cm, 95% CI = −0.85 to −0.08) in the Salta sample. Toxic elements concentrations were not associated with birth outcomes in Ushuaia participants. Birth outcomes are multifactorial problems, and these findings provide a foundation for understanding how the body burden of toxic and essential elements, within the socioeconomic context, may influence birth outcomes.

Biotransformation of inorganic arsenic: Influence of gender, arsenic dose level, and creatinine formation

Article

Full-text available

Jul 2021

Uttam Chowdhury

Introduction In different countries of the world including Mexico, arsenic concentration in ground water is much higher than accepted levels1. The Lagunera Region of north central Mexico has arsenic problem in groundwater with significant resulting chronic health problems2. An important limitation on the scientific understanding of arsenic toxicity is the complexity of arsenic metabolism. Differences in susceptibility to arsenic toxicity might be manifested by differences in arsenic metabolism or in the prevalence of arsenic-associated diseases among people of either gender, ages, nutritional factors, polymorphisms of the arsenic biotransformation genes in different ethnic group3,4 and may other unknown factors. Previous studies indicated that females are less susceptible to the arsenic related skin effects than males5-7. Inorg-As is metabolized in the body by alternating reduction of pentavalent arsenic to trivalent form by enzymes and addition of a methyl group from S-adenosylmethionine3,8; it is excreted mainly in urine as DMA (V)9. Inorganic arsenate [Inorg-As (V)] is biotransformed to Inorg-As (III), MMA (V), MMA (III), DMA (V), and DMA (III) (Fig. 1)3. Therefore, the study of the toxicology of Inorg-As (V) involves at least these six chemical forms of arsenic. Studies reported the presence of 3+ oxidation state arsenic biotransformants [MMA (III) and DMA (III)] in human urine10 and in animal tissues11. The MMA (III) and DMA (III) are more toxic than other arsenicals12,13. In particular MMA (III) is highly toxic12,13. In increased % MMA in urine has been recognized in arsenic toxicity14. In addition, people with a small % MMA in urine show less retention of arsenic15. Thus, the higher prevalence of toxic effects with increased % MMA in urine could be attributed to the presence of toxic MMA (III) in the tissue. Previous studies also indicated that males are more susceptible to the As related skin effects than females14,16. A study in the U.S population reported that females excreted a lower % Inorg-As as well as % MMA, and a higher % DMA than did males17. Figure 1. Metabolism of Inorg-As. Gamble et al. (2008)18 has found that higher urinary creatinine is associated with reduced risk for premalignant skin lesions among the arsenic exposed population in Bangladesh and folic acid supplementation significantly increased urinary creatinine. It is well known that the concentrations of pollutants in spot urine sample are highly dependent on the dilution of the sample caused by variation in the intake of fluids, physical activity, temperature, etc19. Commonly applied method to control for this variation is adjustment by the creatinine concentration in urine19-21. However, creatinine is a waste product formed by the spontaneous, essentially irreversible dehydration of body creatine and creatine phosphate from muscle metabolism and meat intake20-23. Thus, urinary creatinine (U-cre) varies by gender, age, body size, racelethnicity, diet, renal function, etc20,24,25. Recent studies have been reported that urinary arsenic levels (µg/L) were found significantly correlated with urinary creatinine levels26,27. Hindwood et al. (2002) has been suggested that creatinine adjustment of urinary inorganic arsenic (Inorg-As) concentrations may not be required in population studies investigating environmental exposure. In this study, we investigated the influence of gender, creatinine, and total arsenic concentrations on the percentage of arsenic metabolites in urine as well as blood among the population in Lagunera area of Mexico, who drunk arsenic concentration above 10 µg/L (range: 38-116 µg/L). Our results indicate that more efficient methylation of arsenic in females compared to males. Total arsenic in urine, in blood as well as urinary creatinine concentrations were negatively associated with % inorg As as well as % MMA, but positively associated with % DMA in urine for both females and males. Materials and Methods Reagents. The chemicals used and there sources are as follows: Sodium arsenate (ACS reagent grade) from MCB Reagents (Cincinnati, OH); dimethylarsinic acid (sodium salt), ammonium phosphate (dibasic), and arsenobetaine from Sigma Chemical Co. (St. Louis, MO); sodium m-arsenite and ammonium nitrate from Sigma-Aldrich Co. (St. Louis, MO); disodium methyl arsenate from ChemService, Inc. (West Chester, PA). The arsenic standard solution was from SPEX Certiprep (Metuchen, NJ). Freeze-dried urine reference material for toxic elements (SRM 2670a) and frozen bovine blood reference material for toxic metals (SRM 966) from National Institute of Standards & Technology (NIST, Gaithersburg, MD 20899). Triton X-100 from Pharmacia Biotech (Uppsala, Sweden). All other chemicals were analytical reagent grade or the highest quality obtainable. Water was doubly deionized and distilled. Subjects. Urine and blood samples were collected from 191 subjects (98 females and 93 males), aged 18-77 years in the Lagunera area of Mexico. There were five groups, based on total arsenic concentrations (38-116 µg/L) in their drinking water. Urine and blood collection. All collecting containers were soaked overnight in 2% nitric acid (Baker analyzed for trace metal analysis) (J. T. Baker, Inc. Phillipsburg, NJ) and rinsed with double distilled and deionized water. All plastic measuring and collecting equipment were similarly washed, sealed in bags, placed in locked footlockers, and transported by air to the site of the study at the same time as the investigators. After collection, urine sample was immediately frozen in a portable icebox containing dry ice. Blood was collected by venous puncture, into Vacutainers containing EDTA, transferred to the vial, and immediately frozen. The samples were kept frozen while being transported to the University of Arizona, Tucson where they were stored at -70°C before analysis. Separation techniques of urinary arsenic metabolites. Arsenic contamination in drinking water is the reason for the elevated levels of arsenic in urine. Even arsenic from seafood (arsenobetaine, As B) may be responsible for the elevated levels of arsenic in urine. Thus, to know the nature of arsenic contamination and the measurement of arsenic metabolites, HPLC-ICP-MS is the most advance and reliable technique. The method of Gong et al. (2001)28 could not separate As B and As B was overlapped with arsenite (Figs. 2B & 2D). In this study, an HPLC-ICP-MS method29 was modified by author for the measurement of arsenic metabolites including As B in urine (Figs. 2C & 2D). One of the urine sample (sample ID # 141) contained very high level of arsenic (697 µg/L urine) due to As B (509 µg/L urine, i.e., 73% of total arsenic; Fig. 2D) and we were excluded this sample from our results. Figure 2: HPLC methods for separation of urinary arsenic metabolites. Method 1: The method of Gong et al. (2001)28 and Method 2: The modified method of Reuter et al. (2003)29. Arsenic species/metabolites analysis. Frozen urine samples were thawed at room temperature, filtered with a 0.45 µm filter (Nanosep MF Centrifugal Devices, Pall Life Sciences, Ann Arbor, MI), and diluted 5-fold using Milli-Q water before injection. An HPLC-ICP-MS (High Performance Liquid Chromatography Inductively Coupled Plasma-Mass Spectrometry) speciation method29 was modified for the measurement of arsenic concentrations. The HPLC system consisted of a PerkinElmer Series 200 HPLC with an anion exchange column (Gemini PRP-X100, 10µm, 250 X 4.6mm, Hamilton Company, Nevada). The mobile phase (pH 8.5) contained 10 mM ammonium nitrate and 10 mM ammonium phosphate (dibasic) at a flow rate of 1 ml/min. The column temperature was maintained at 30° C. An ELAN DRCE ICP-MS (Perkin-Elmer) with a cyclonic quartz spray chamber and Meinhard nebulizer was used as a detector for the analysis of arsenic species [As B, AS (V), As (IlI), MMA (V), and DMA (V)] in urine at 4° C. The operating parameters were as follows: Rf power, 1400 W; plasma gas flow, 15 L/min; nebulizer gas flow, 0.82 L/min; auxiliary gas flow, 1.2 L/min; oxygen flow for DRC, 0.87 mL/min; and arsenic was measured at miz 91. The working detection limits were 0.80 - 1.75 µg/L for arsenic metabolites. Accuracy values were calculated by spiking standard compounds of all five species (5 µg/L) in urine samples. The recoveries of the added compounds were 98-103%. Standard samples (5 µg/L) containing all five arsenic species were also analyzed after analysis the urine samples each day. The values of mean ± SE for As B, As (V), AS (III), MMA (V), and DMA (V) were found 4.86 ± 0.08, 5.09 ± 0.11, 5.16 ± 0.11, 5.02 ± 0.10, and 4.90 ± 0.05 µg/L, respectively. Total arsenic analysis in urine samples. Urine samples in acid washed polypropylene tubes were digested with nitric acid (5: 1) while a water bath for 40 min at 70° C. Freeze-dried urine reference material for toxic elements containing arsenic at a level of 220 ± 10 µg As/L was used for quality control and to validate the assay. After acid digestion, analysis of this standard by ICP-MS yielded a range of 216.0 - 236.0 µg As/L with a range of recoveries of 98.18 - 107.27 %. We also analyzed the spiking standard compounds of all the arsenic species [As B, As (V), AS (IlI), MMA (V), and DMA (V)] at levels of 10 µg total As /L and 20 µg total As/L. The recoveries of the spiking samples were 104.20 % (10.42 ± 0.13 µg As/L) and 97.70 % (19.54 ± 0.24 µg As/L), respectively. After acid digestion, analyzed trace elements in urine samples collected from the subjects and NIST reference urine samples. The recoveries of Se, Zn, Co, Cu, Mn, Ni, Cd, Pb, and Hg in NIST reference urine were 92.16 %, 93.01 %, 101.00 %, 94.77 %, 106.06 %, 100.84 %, 109.70 %, 100.72 %, and 94.28 %, respectively. The multi-element standard solutions were digested and diluted using the same procedure and dilution factors (as the samples) for preparation of the calibration curve. The calibration correlation coefficients (r2) of the elements were greater than 0.999. Total arsenic analysis in whole blood samples. Whole blood samples were analyzed for total As concentrations using Perkin Elmer Elan DRCe ICP-MS. Inductively coupled plasma mass spectrometry method for elements in whole blood was developed (with modifications) based on published method30. Whole blood samples were thawed, thoroughly mixed, diluted 50 times with diluents containing 0.65% HNO3 + 0.1% Triton X-100, and centrifuged for 10 min (3500 rpm at 4° C) with the supernatant reserved for analysis. The multi-element standard solutions were prepared from stock standard solution with 0.65% HNO3 + 0.1% Triton X-100. The rinse solution contained 2% HNO3 + 1% Triton X-100. The calibration correlation coefficients (r2) of the elements were greater than 0.999. Frozen bovine blood reference material for toxic metals was used for quality control and to validate the assay. The reference sample was thawed in ice, mixed thoroughly, and diluted 50 times with diluents containing 0.65% HNO3 + 0.1% Triton X-100, and centrifuged for 10 min (3500 rpm at 4° C) with the supernatant reserved for analysis. The recoveries of Pb, Cd, and Hg in the reference bovine blood samples were 92 %, 107 %, and 97 %, respectively. The certified values of As was not available. We also analyzed the spiking standard elements in the human blood samples and also the quality control (QC) standard samples. The spiking and QC samples were prepared and analyzed using the same procedures as the human blood samples. The recoveries of the elements in the spiking and QC samples were very close to the spiking and QC standard values. Creatinine measurement. Creatinine (cre) concentration in urine sample was determined using the Randox Creatinine Colorimetric kit (San Diego, CA), which is based on the reaction of creatinine with picric acid in alkaline solution, forming a colored complex, and measured at 492 nm31. Statistical analysis: The mean and standard error (SE) were calculated. The unpaired t test (Graph Pad Software, Inc., 2005) was used to analyze the significance difference. The correlation coefficients for different variables were tested using the Spearman rank order correlation test (Richard Lowry, 1998, 2008). P values less than 0.05 (two-tailed) were considered significant. Results Study population. In this study, out of 191 participants in Lagunera area of Mexico, 98 were females (F) and 93 were males (M). The average age of females versus males was not statistically significant (Table 1). There were five groups of participants based on total arsenic concentration in their drinking water. The concentrations of As in drinking water were positively associated with urinary total As (mean values) of different groups of population (Figs. 3 and 4). Table 1. The study population in Lagunera area of Mexico. Figure 3: The correlation between total arsenic in drinking water and total arsenic in urine samples (after acid digestion) of different groups of population. Figure 4: The correlations between total arsenic in drinking water and total arsenic in urine samples (after acid digestion) of females and males from different groups of population. Urinary arsenic metabolites. The distribution of the percentage (%) of arsenic metabolites [As B, As (V), AS (III), MMA (V), and DMA (V)], sum of arsenic metabolites (As Sum), and total arsenic (Total As) in urine (after acid digestion) of different groups of population were shown in the Fig. 5. The mean values of sum of arsenic metabolites and total arsenic in urine samples of individual groups of population were very close. Figure 5: Distribution of the percentage of arsenic metabolites, sum of arsenic metabolites, and total arsenic in urine samples (after acid digestion) of different groups of study population. Gender differences in the distribution of urinary arsenic metabolites. Urinary arsenic metabolites measured of 191 participants showed a wide inter-individual variability in arsenic methylation capacity. Fig. 6 shows that the highest percentage of females (33 %) had the percentage of inorganic arsenic (% Inorg-As = % As (III) + % As (V)) ranged from 10 to 15 % and males (28.72 %) had ranged from 15 to 20 %. The percentage of MMA (% MMA) ranged from 5 to 10 % had 44.9% of females population and ranged from 10 to 15 % had 44.68 % of males population. On the other hand, the percentage of DMA (% DMA) ranged from 80 to 90 % had 36.73 % of females and ranged from 70 to 80 % had 39.78 % of males population. The percent of DMA ranged from 35.46 to 94.21 %, with the majority of the participants falling ranged from 60 to 90 %. Figure 6: Frequency distribution of arsenic metabolites in urine of females and males. Overall results show that female participants had less % inorg-As as well as % MMA, and higher % DMA in urines compared to male participants. The mean values of % inorg As, % MMA, and % DMA in urines for females were 15.13 ± 0.76, 9.43 ± 1 0.48, and 73.97 ± 1.16 %, respectively and for males were 16.75 ± 0.76, 11.71 ± 0.45, and 69.71 ± 0.99 %, respectively. The results indicated that methylation capacity differed by sex: on average, females had a lower % MMA than males (9.43 ± 0.48 vs. 11.71 ± 0.45 % MMA, respectively, p<0.01) and a higher % DMA (73.97 ± 1.16 vs. 69.71 ± 0.99 % DMA, respectively, p< 0.01). The % inorg-As did not significantly differ by sex (15.13 ± 0.76 vs. 16.75 ± 1 0.76 % inorg As, respectively, p= 0.14). The mean value of the ratios of % MMA to % inorg-As was significantly lower and the mean value of the ratios of % DMA to % MMA was significantly higher in urine for females compared to males (0.69 ± 0.04 vs. 0.82 ± 0.05, p<0.05, and 10.35 ± 0.69 vs. 7.26 ± 0.45, p≤0.01, respectively). Our overall results indicate that second methylation step was more active and first methylation step was less active in females compared to males. The mean value of the ratios of % DMA to % inorg As was also significantly higher in urines for females compared to males (p<0.05). The correlation between drinking water arsenic concentrations and urinary arsenic as well as blood arsenic concentrations. Total arsenic concentrations in drinking water expressed as µg/L were positively and strongly correlated with arsenic concentrations in urine expressed as µg/L (rs= +0.56, p<0.01) or µglg cre (rs= +0.64, p<0.01) as well as blood expressed as µg/L (rs= +0.65, p<0.01) of this study population (Fig. 7). Blood arsenic concentrations were also positively correlated with urinary total arsenic concentrations expressed as µg/L (rs= +0.56, p<0.01) or µg/g cre (rs= +0.68, p<0.01). Figure 7: Correlation between As in drinking water and As in urine as well as blood of arsenic exposed people in Lagunera area of Mexico. The correlations between arsenic concentrations in urine as well as blood and percentage of urinary arsenic metabolites. The correlations between arsenic concentrations in urine as well as blood and percentage of urinary arsenic metabolites for females and males are shown in Table 2 and Fig. 8. Table 2. Spearman correlation coefficients (rs) between urinary as well as blood arsenic concentrations and percentage of urinary arsenic metabolites for females and males. ap<0.05,bp<0.01,cp<0.001,dp<0.00001, ep<0.000001 The concentrations of arsenic in urine expressed as µg/L or µg/g cre and arsenic concentrations in blood expressed as µg/L were negatively associated with % inorg As (rs= -0.54, p<0.000001; rs= -0.27, p<0.01, and rs= -0.32, p<0.01, respectively) as well as % MMA (rs= -0.43, p<0.00001; rs= -0.28, p<0.01, and rs= -0.26, p<0.05, respectively), and positively associated with % DMA (rs= +0.54, p<0.000001; rs= +0.28, Figure 8. The correlation between urinary arsenic metabolites and urinary total arsenic (sum of arsenic metabolites). p<0.01, and rs= +0.29, p<0.01, respectively) in urine for females. The ratios of % DMA to % MMA in urine were also positively and significantly correlated with arsenic concentrations in urine as well as blood (rs= +0.47, p<0.00001; rs= +0.31, p<0.01, and rs= +0.30, p<0.01, respectively) for females. For males, arsenic concentrations in urine expressed as µg/L or µg/g cre and arsenic concentrations in blood expressed as µg/L were also negatively correlated with % inorg As, (rs= -0.49, p<0.000001; rs= -0.24, p<0.05, and rs= -0.25, p<0.05, respectively), and positively correlated with % DMA (rs= +0.50, p<0.000001; rs= +0.29, p<0.01, and rs= +0.28, p<0.01, respectively). The percentage of MMA (% MMA) was not significantly correlated with arsenic concentrations in urine expressed as µg/g cre or in blood expressed as µg/L for males. The ratios of % MMA to % inorg As in urine were positively and significantly correlated with arsenic concentration in blood (rs= +0.22, p<0.05) and As concentrations in urine expressed as µg/L (rs= +0.21, p<0.05) for males, but not with arsenic concentrations in urine expressed as µg/g cre. The correlations between the ratios of % DMA to % MMA and arsenic concentrations in urine expressed as ug/g cre or in blood expressed as ug/L were not statistically significant for males. We also found that the correlation coefficients between arsenic concentrations in blood expressed as µg/L and the percentage of urinary arsenic metabolites were very close to the correlation coefficients found between urinary arsenic concentrations expressed as µg/g cre and the percentage of urinary arsenic metabolites for both females and males. Concentrations of total arsenic in urine expressed as µg/L versus µg/g cre for females and males. Urinary total arsenic concentrations (after acid digestion) expressed as µg/L were significantly lower for females compared to males (p<0.01) (Table 3). But after urinary creatinine adjustment, urinary total arsenic concentration expressed as µg/g cre was not significantly difference between females and males (p=0.14). This was due to significant sex differences in urinary creatinine concentrations and urinary creatinine concentrations were significantly higher for males than females (p<0.0001). Urinary creatinine concentrations were not significantly correlated with ages for both females and males participants in the Lagunera area of Mexico. Table 3. Urinary arsenic (U-As) and urinary creatinine (U-cre) concentrations for females (F) and males (M). Values are the Mean ± SE. The correlation between urinary total arsenic as well as blood total arsenic concentrations and urinary creatinine (U-Cre) concentrations. Urinary arsenic concentrations were positively associated with urinary creatinine (r= +0.801, p=0.000001) (Fig. 9). This positive correlation was more strong in males (r= +0.823, p<0.000001) compared to females (r= +0.771, p=0.000001). Figure 9: Correlation between Log urinary arsenic as well as blood and Log U-cre concentrations. The correlation between urinary creatinine concentrations and percentage of urinary arsenic metabolites. The results show (Fig. 10) that urinary creatinine concentrations (g/L) were negatively associated with % inorg As as well as % MMA in urines for both females (rs= -0.59, p<0.000001 and rs= -0.34, p<0.01, respectively) and males (rs= - 0.45, p<0.00001 and rs= -0.39, p<0.0001, respectively). But urinary creatinine concentrations were more positively associated with % DMA in urines for females (rs= +0.56, p<0.000001) compared to males (rs= +0.41, p<0.0001). The ratios of % MMA to % inorg As and the ratios of % DMA to % MMA were positively associated with creatinine in urines for both females and males (Table 4). This positive correlation was stronger for the ratios of % DMA to % MMA (females: rs= +0.43, p<0.01 and males: rs= +0.46, p<0.01) than the ratios of % MMA to % inorg As (females: rs= +0.26, p<0.01 and males: rs= +0.14, p=0.167). Figure 10. The correlation between percentage (%) of urinary arsenic metabolites and urinary creatinine (mg/L). Table 4. Spearman correlation coefficients (rs) between urinary creatinine concentrations (g/L) and percentage of urinary arsenic metabolites for females and males. ap<0.01, bp<0.001, cp<0.0001, dp<0.00001, ep<0.000001 Discussion The present study clearly shows that the participants in the Lagunera area of Mexico had remarkably influenced of sex, dose level, and urinary creatinine concentrations on the percentage of arsenic metabolites in urine. The study also shows that urinary creatinine adjustment may be highly over estimated of urinary arsenic concentrations especially for females. Sex differences in urinary arsenic metabolites. An important finding of interest in our observation that metylation capacity differed by sex: females had a significantly lower % MMA and a higher % DMA in urine compared to males. The ratios of % MMA to % inorg As and the ratios of % DMA to % MMA were also significantly lower and significantly higher in urines for females compared to males, respectively. The results suggest that arsenic methylation capacity was higher in females compared to males. In our knowledge, this will be the first reporting that the efficiency of arsenic methylation was significantly higher in females compared to males who drunk water contain low level of arsenic (range 38-116 µg/L) and not showing arsenic related skin effects in Mexican. One study of human exposure to arsenic via drinking water (up to 600 µg/L) in northeastern Taiwan also indicated that females had a higher % DMA and a lower % MMA in urines than males32. Another study of human exposed to high arsenic concentrations in drinking water in Bangladesh found a higher fraction of MMA and a lower fraction of DMA in urines among males as compared to females6. A study in the U.S. population reported that females excreted a lower % inorg As as well as % MMA, and a higher % DMA than did males17. Another study in Mexican people showing skin effects due to exposure to arsenic via drinking water had a higher % MMA and a lower % DMA in urines than those without such effects2. However, they did not compare the % MMA and % DMA in urines for females and males, separately. In our results, it also appears that first methylation reaction is less active and second methylation reaction is more active in females compared to males of inorganic arsenic biotransformation process. This means that inorganic arsenic converted to MMA faster in males compared to females. But, MMA converted to DMA faster in females than males, and a higher proportion of DMA and a lower proportion of MMA found in urines for females as compared to males. The results suggest and support that more than one methylase may be involved in the oxidative methylation of inorg As3,11,33. A slow second methylation reaction in combination with a faster first methylation reaction seems to be most critical from a toxicological point of view. Higher proportion of MMA in urines, probably higher concentrations of the highly reactive and toxic MMA (III) in the tissues34,35 leading to a higher retention of arsenic in the body36-38. Previous studies reported that females are less susceptible to the arsenic-related skin effects than males5-7,39. May be, due to higher methylation capacity and lower retention of arsenic (specially, MMA (III)] in the tissues, females are less susceptible to the arsenic-related skin effects compared to males. Additionally, the two steps of arsenic methylation efficiency involving different methylated metabolites with different concentrations in individuals may likely have distinct features of arsenic health effects. S-adenosylmethionine (SAM) is the main methyl donor for arsenic menylation reactions40. Another important methyl donor, besides SAM, is choline, which could either be derived from the diet or from phosphatidylcholine. Experimental studies on rabbits fed diets with low amounts of choline or methionine, have shown a marked decrease in the urinary excretion of DMA41. Recent studies have indicated that the synthesis of phosphatidylcholine is up regulated by estrogen42. Possibly, explaining the better methylation of arsenic among females compared to males is related to the higher endogenous production of choline in females, which after oxidation to betaine is the sole alternate methyl group to folate for the remethylation of homocysteine to methionine43,44. Elevated homocysteine levels, which are indicative of a lower one carbon metabolism, are associated with less efficient methylation of arsenic45 and elevated plasma homocysteine level was correlated with high levels of % MMA in urine46. S-adenosylhomocysteine (SAH) is an inhibitor of the activity of many methyltransferase47 and it has been reported that SAH decreased methylation of arsenite, especially DMA production48. It was also reported that arsenic methylation is induced during pregnancy6,49 and may be sex hormones play an important role for arsenic methylation. Another important explaining for the efficient second metylation of arsenic in females compared to males is most likely genetic polymorphisms in genes coding for enzymes involved in arsenic methylation3. In near future this will be cleared the mechanisms of arsenic methylation involving sex hormones. Influence of arsenic doses on urinary arsenic metabolites. The association between arsenic concentrations in drinking water and urines had a positive linear coefficient of +0.56. The drinking water As (WAs) concentrations (µg/L) were positively and strongly correlated with blood arsenic (BAs) concentrations (µg/L) for both females and males. BAs concentrations (µg/L) were also positively and strongly correlated with urinary arsenic (UAs) concentrations expressed as µg/L as well as µg/g cre for both females and males. Similarly to our findings, Hall et al. (2006)50 found a strong positive correlation between BAs and UAs, and both were positively and significantly correlated with WAs. Our results show that urinary as well as blood As concentrations were negatively correlated with urinary % inorg As as well as % MMA, and positively correlated with % DMA, the ratios of % MMA to % inorg As as well as the ratios of % DMA to % MMA for both females and males. These results indicated that the methylation of arsenic was increased (specially, second methylation reaction) with increasing urinary arsenic, i.e., increasing arsenic concentration in drinking water (38- 116 µg/L) of our study population. A number of experimental studies on human subjects receiving specified doses of inorganic arsenic, indicated that the urinary excretion of total arsenic metabolites increased with decreasing % inorg As as well as % MMA but increasing % DMA in urine51-54. Influence of urinary creatinine concentrations on urinary arsenic metabolites. A number of significant correlations were observed regarding urinary arsenic metabolites and urinary creatinine concentrations in this study. Urinary creatinine was negatively associated with % inorg As as well as % MMA, and positively associated with % DMA in urine for both females and males. Urinary creatinine concentrations were also positively and strongly associated with the ratios of %DMA to %MMA, but not significantly associated with the ratios of %MMA to %inorg As in urine for both females and males. The results indicate that there are some difference mechanisms between the first methylation reaction and the second methylation reaction of arsenic biotransformation process. Gamble et al. (2005)26 also observed that urinary creatinine concentrations were positively and significantly associated with % DMA for both females and males, and negatively associated with % inorg As as well as % MMA in urines for females only. Other researchers have not been reported significant correlation between creatinine concentrations and % MMA in urine for males with the exception of our observation in this study. Creatinine is derived from creatine and creatine phosphate in muscle tissue. It is produced and excreted from the body in the urine via the kidney at a constant rate which is proportional to the body muscle mass20. In our study, the association between urinary creatinine concentrations and the percentage of arsenic metabolites were remarkable. The urinary creatinine concentration was significant predictor of arsenic methylation for both females and males. The urinary creatinine concentration is highly correlated with muscle mass20,55 and may have some unknown impact on arsenic methylation process. Boeniger et al. (1993)56 reported that 15-20% of the creatinine in urine could occur by active secretion from the blood through the renal tubules, i.e., urinary creatinine is influenced by renal function, which could have some unclear function for arsenic methylation process. Studies are needed to know the mechanisms of the correlation between creatinine formation and arsenic methylation process in humans. Conclusions. The results of this study suggest to conclude the following information: (i) More efficient methylation of arsenic among females compared to males of the population in the Lagunera area of Mexico, who drunk arsenic concentration above 10 ug/L (range: 38-116 µg/L), (ii) Due to slower 'first methylation reaction' and faster 'second methylation reaction', females may less susceptible to arsenic-related skin effects compared to males5-7, (iii) The methylation of arsenic was increased (specially, second methylation reaction) with increasing urinary arsenic, i.e., increasing arsenic concentration in drinking water, (iv) Creatinine formation may influence arsenic metabolisms with unknown mechanisms, and we need to study for understanding of these mechanisms, and (v) Data from females and males should be reported separately. Acknowledgement: The Author wants to dedicate this paper to the memory of Dr. H. Vasken Aposhian and Mary M. Aposhian who passed away in September 6, 2019 and September 9, 2009, respectively. H. Vas Aposhian and M. M. Aposhian had collected these urine and blood samples from people in the Lagunera area of Mexico. Also, this research work was done under Prof. Vas Aposhian sole supervision and with his great contribution. The Superfund Basic Research Program NIEHS Grant Number ES 04940 from the National Institute of Environmental Health Sciences and the Southwest Environmental Health Sciences Center P30-ES-06694 supported this work. References: Smedley, P.L., Kinniburgh D.G., 200 A review of the source, behavior, and distribution of arsenic in natural waters. Appl. Geochem. 17, 517-568. Del Razo, L.M., Garcia-Vargas, G.G., Vargas; H., Albores, A., Gonsebatt; M.E., Montero, R., Ostrosky-Wegman, P., Kelsh, M., Cebrian, M.E., 1997. 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Early pregnancy exposure to metal mixture and birth outcomes – A prospective study in Project Viva

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Nov 2021
ENVIRON INT

Background Prenatal exposure to metals has been individually associated with birth outcomes. However, little is known about the effect of metal mixture, particularly at low exposure levels. Objectives To estimate individual and joint effects of metal mixture components on birth outcomes. Methods We used data from 1,391 mother-infant pairs in Project Viva (1999–2002). We measured 11 metals in maternal 1st trimester erythrocyte; abstracted birth weight from medical records; calculated gestational age from last menstrual period or ultrasound; and obtained birth length (n = 729) and head circumference (n = 791) from research measurements. We estimated individual and joint effects of metals using multivariable linear and Bayesian kernel machine regressions. Results In both single metal and metal mixture analyses, exposure to higher concentrations of arsenic was associated with lower birth weight in males, zinc with higher head circumference in females, and manganese with higher birth length in sex-combined analysis. We also observed sex-specific metal interactions with birth outcomes. Arsenic and manganese showed a synergistic association with birth weight in males, in whom an interquartile range (IQR) increase in arsenic was associated with 25.3 g (95% CI: −79.9, 29.3), 47.9 g (95% CI: −98.0, 2.1), and 72.2 g (95% CI: −129.8, −14.7) lower birth weight when manganese concentrations were at 25th, 50th, and 75th percentiles, respectively. Lead and zinc showed an antagonistic association with head circumference in males, where an IQR increase in lead was associated with 0.18 cm (95% CI: −0.35, −0.02), 0.10 cm (95% CI: −0.25, 0.04), 0.03 cm (95% CI: −0.2, 0.14) smaller head circumference when zinc concentrations were at 25th, 50th, and 75th percentiles, respectively. Exposure to higher concentrations of arsenic was also associated with lower gestational age in males when concentrations of manganese and lead were higher. Discussion Maternal erythrocyte concentrations of arsenic, manganese, lead, and zinc were individually and interactively associated with birth outcomes. The associations varied by infant sex and exposure level of other mixture components.

Arsenic exposure through drinking groundwater and consuming wastewater-irrigated vegetables in Multan, Pakistan

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Dec 2021
ENVIRON GEOCHEM HLTH

Arsenic (As) is one of the most toxic metalloids for humans. Above permissible levels of As cause severe health implications. Contaminated drinking water and food items may be the leading sources of As exposure to people all around the world. The current study assessed the levels of As in drinking water, vegetables, irrigation water, agricultural soils, and the human population (adult women and men) of rural and peri-urban areas of Multan (Pakistan). For a comparison between peri-urban (exposed site) and rural areas (control site), we sampled irrigation water, vegetables and vegetable-grown soils, drinking water, and human blood. In all sample types, As concentration was significantly higher at exposed site than at control site. Alarmingly, As concentration in drinking groundwater (34 µg As L⁻¹) of exposed site was 3.4-folds higher than the permissible limit (set by WHO). Among the studied vegetables, the cumulative daily dietary intake of As was recorded maximum by the consumption of okra (474 ng d–1 on exposed site) and minimum by long melon (1 ng d–1 on control site). However, As intake via drinking water was estimated to contribute ≥ 98% of total As intake at both sites. Hence, the health risks associated with drinking As-contaminated groundwater were recorded much higher than the health risks associated with the consumption of As-contaminated vegetables. Blood As levels in most of the subjects at exposed site exceeded the safe limit of 12 µg L⁻¹. Conclusively, the findings of the current study indicated that drinking contaminated groundwater may be the major cause of As-associated health risks in the region.

Association between body mass index and arsenic methylation in three studies of Bangladeshi adults and adolescents

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Apr 2021
ENVIRON INT

Background Water-borne arsenic (As) exposure is a global health problem. Once ingested, inorganic As (iAs) is methylated to mono-methyl (MMA) and dimethyl (DMA) arsenicals via one-carbon metabolism (OCM). People with higher relative percentage of MMA (MMA%) in urine (inefficient As methylation), have been shown to have a higher risk of cardiovascular disease and several cancers but appear to have a lower risk of diabetes and obesity in populations from the US, Mexico, and Taiwan. It is unknown if this opposite pattern with obesity is present in Bangladesh, a country with lower adiposity and higher As exposure in drinking water. Objective To characterize the association between body mass index (BMI) and As methylation in Bangladeshi adults and adolescents participating in the Folic Acid and Creatine Trial (FACT); Folate and Oxidative Stress (FOX) study; and Metals, Arsenic, and Nutrition in Adolescents Study (MANAS). Methods Arsenic species (iAs, MMA, DMA) were measured in urine and blood. Height and weight were measured to calculate BMI. The associations between concurrent BMI with urine and blood As species were analyzed using linear regression models, adjusting for nutrients involved in OCM such as choline. In FACT, we also evaluated the prospective association between weight change and As species. Results Mean BMIs were 19.2/20.4, 19.8/21.0, and 17.7/18.7 kg/m² in males/females in FACT, FOX, and MANAS, respectively. BMI was associated with As species in female but not in male participants. In females, after adjustment for total urine As, age, and plasma folate, the adjusted mean differences (95% confidence) in urinary MMA% and DMA% for a 5 kg/m² difference in BMI were −1.21 (−1.96, −0.45) and 2.47 (1.13, 3.81), respectively in FACT, −0.66 (−1.56, 0.25) and 1.43 (−0.23, 3.09) in FOX, and −0.59 (−1.19, 0.02) and 1.58 (−0.15, 3.30) in MANAS. The associations were attenuated after adjustment for choline. Similar associations were observed with blood As species. In FACT, a 1-kg of weight increase over 2 to 10 (mean 5.4) years in males/females was prospectively associated with mean DMA% that was 0.16%/0.19% higher. Discussion BMI was negatively associated with MMA% and positively associated with %DMA in females but not males in Bangladesh; associations were attenuated after plasma choline adjustment. These findings may be related to the role of body fat on estrogen levels that can influence one-carbon metabolism, e.g. by increasing choline synthesis. Research is needed to determine whether the associations between BMI and As species are causal and their influence on As-related health outcomes.

Effects of arsenic exposure on blood trace element levels in rats and sex differences

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Apr 2024
BIOMETALS

Arsenic (As) is a widespread environmental metalloid and human carcinogen, and its exposure is associated with a wide range of toxic effects, leading to serious health hazards. As poisoning is a complex systemic multi-organ and multi-system damage disease. In this study, a rat model of As poisoning was established to investigate the levels of trace elements in the blood of rats and sex differences in the effect of As on every trace elements in rat blood. Twenty 6-week-old SD (Sprague Dawley) rats were randomly divided into the control group and the As-exposed group. After 3 months, the contents of 19 elements including As in the blood were detected in these two groups by inductively coupled plasma mass spectrometry (ICP-MS). As levels in the blood of As-exposed rats were significantly higher than those in the control group, with increased levels of Rb, Sr, Cs and Ce, and decreased levels of Pd. As showed a significant positive correlation with Rb. There were significant sex differences in blood Se, Pd, Eu, Dy, Ho, and Au levels in the As-exposed group. The results showed that As exposure can lead to an increase of As content in blood and an imbalance of some elements. There were sex differences in the concentration and the correlation between elements of some elements. Elemental imbalances may affect the toxic effects of As and play a synergistic or antagonistic role in As toxicity. Graphical abstract Effects of arsenic exposure on trace elements in blood of SD rats, there were sex differences in the blood concentrations of some elements in the As-exposed group. Blood concentrations of some elements changed in the As-exposed group, while correlations were found between some elements. ↑: increased in the As-exposed group. ↓: decreased in the As-exposed group

Stool as a novel biomarker for arsenic exposure through diet: a case-control study in a West Bengal population

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Full-text available

Jan 2024

Geogenic groundwater arsenic (As) contamination is a persistent health threat in the district of Nadia, West Bengal India. Despite provision of safe piped water, local populations in these areas are still exposed to As through diet as the cultivation is majorly dependent on As contaminated shallow groundwater causing significant As accumulation in agricultural foodstuffs. Although urine is an established biomarker for As exposure through drinking water yet, it does not reflect the actual exposure through diet. Hence, stool-As concentration of exposed population should be evaluated to assess the true exposure through diet. The present case-control study evaluates As concentration in stool samples of exposed (n = 24) and unexposed (n = 36) populations. Average stool-As concentration found was 234 ± 207 µg/kg in exposed population while only 66 ± 22 µg/kg in control samples; comparable to those of urine samples of case and control; respectively. Positive Pearson correlation and a significant difference of variance through ANOVA (p = 0.01; F crit = 1.65) among stool-As, urine-As, groundwater-As, age and BMI found for case samples indicate that stool also presents comparable and measurable As concentrations upon exposure. Mann-Whitney U test confirms that random values of stool-As in case samples varied significantly (p < 0.001) than those of control samples. Besides, multi-metal analysis of stool digest indicated that stool-As correlated negatively with most of the metals in case and positively with control samples. These observations along with ease of collection and detection due to higher concentration in the matrix, suggest that stool may act as a decisive biomarker of As exposure through diet. To the best of our knowledge, this is a pioneering study to establish stool as a reliable and significant biomarker for assessing As exposure as limited investigations exist focused on human faecal samples on long term naturally exposed adult human population.

Anthropometric measures and arsenic methylation among pregnant women in rural northern Bangladesh

Article

Jun 2023
ENVIRON RES

Introduction: Arsenic methylation converts inorganic arsenic (iAs) to monomethyl (MMA) and dimethyl (DMA) arsenic compounds. Body mass index (BMI) has been positively associated with arsenic methylation efficiency (higher DMA%) in adults, but evidence in pregnancy is inconsistent. We estimated associations between anthropometric measures and arsenic methylation among pregnant women in rural northern Bangladesh. Methods: We enrolled pregnant women (n = 784) (median [IQR] gestational week: 14 [13, 15]) in Gaibandha District, Bangladesh from 2018 to 2019. Anthropometric measures were BMI, subscapular and triceps skinfold thicknesses, and mid-upper arm circumference (MUAC), fat area (MUAFA), and muscle area (MUAMA). Arsenic methylation measures were urinary iAs, MMA, and DMA divided by their sum and multiplied by 100 (iAs%, MMA%, and DMA%), primary methylation index (MMA/iAs; PMI), and secondary methylation index (DMA/MMA; SMI). In complete cases (n = 765 [97.6%]), we fitted linear, beta, and Dirichlet regression models to estimate cross-sectional differences in iAs%, MMA%, DMA%, PMI, and SMI per IQR-unit difference in each anthropometric measure, adjusting for drinking water arsenic, age, gestational age, education, living standards index, and plasma folate, vitamin B12, and homocysteine. Results: Median (IQR) BMI, subscapular skinfold thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 21.5 (19.4, 23.8) kg/m2, 17.9 (13.2, 24.2) mm, 14.2 (10.2, 18.7) mm, 25.9 (23.8, 28.0) cm, 15.3 (10.5, 20.3) cm2, and 29.9 (25.6, 34.2) cm2, respectively. Median (IQR) iAs%, MMA%, DMA%, PMI, and SMI were 12.0 (9.3, 15.2)%, 6.6 (5.3, 8.3)%, 81.0 (77.1, 84.6)%, 0.6 (0.4, 0.7), and 12.2 (9.3, 15.7), respectively. In both unadjusted and adjusted linear models, all anthropometric measures were negatively associated with iAs%, MMA%, and PMI and positively associated with DMA% and SMI. For example, fully adjusted mean differences (95% CI) in DMA% per IQR-unit difference in BMI, subscapular skinfolds thickness, triceps skinfold thickness, MUAC, MUAFA, and MUAMA were 1.72 (1.16, 2.28), 1.58 (0.95, 2.21), 1.74 (1.11, 2.37), 1.45 (0.85, 2.06), 1.70 (1.08, 2.31), and 0.70 (0.13, 1.27) pp, respectively. Conclusions: Anthropometric measures were positively associated with arsenic methylation efficiency among pregnant women in the early second trimester.

Toxic elements in arctic and sub-arctic brown bears: Blood concentrations of As, Cd, Hg and Pb in relation to diet, age, and human footprint

Article

Full-text available

Apr 2023
ENVIRON RES

Contamination with Arsenic (As), cadmium (Cd), mercury (Hg) and lead (Pb) is a global concern impairing resilience of organisms and ecosystems. Proximity to emission sources increases exposure risk but remoteness does not alleviate it. These toxic elements are transported in atmospheric and oceanic pathways and accumulate in organisms. Mercury accumulates in higher trophic levels. Brown bears (Ursus arctos), which often live in remote areas, are long-lived omnivores, feeding on salmon (Oncorhynchus spp.) and berries (Vaccinium ssp.), resources also consumed by humans. We measured blood concentrations of As, Cd, Hg and Pb in bears (n = 72) four years and older in Scandinavia and three national parks in Alaska, USA (Lake Clark, Katmai and Gates of the Arctic) using high-resolution, inductively-coupled plasma sector field mass spectrometry. Age and sex of the bears, as well as the typical population level diet was associated with blood element concentrations using generalized linear regression models. Alaskan bears consuming salmon had higher Hg blood concentrations compared to Scandinavian bears feeding on berries, ants (Formica ssp.) and moose (Alces). Cadmium and Pb blood concentrations were higher in Scandinavian bears than in Alaskan bears. Bears using marine food sources, in addition to salmon in Katmai, had higher As blood concentrations than bears in Scandinavia. Blood concentrations of Cd and Pb, as well as for As in female bears increased with age. Arsenic in males and Hg concentrations decreased with age. We detected elevated toxic elements in bears from landscapes that are among the most pristine on the planet. Sources are unknown but anthropogenic emissions are most likely involved. All study areas facvde upcoming change: Increasing tourism and mining in Alaska and more intensive forestry in Scandinavia, combined with global climate change in both regions. Baseline contaminant concentrations as presented here are important knowledge in our changing world.

Association of intronic polymorphisms (rs1549339, rs13402242) and mRNA expression variations in PSMD1 gene in arsenic-exposed workers

Article

Full-text available

Apr 2023
ENVIRON SCI POLLUT R

Ubiquitin-proteasome system (UPS) gene, PSMD1, is an important gene for neutralization of damaged and misfolded protein(s). The current study was designed to study the genetic and expression variations of PSMD1 gene as a consequence of arsenic exposure and its potential implications in arsenic induced diseases. In the present study, 250 blood samples of exposed industrial workers along with 250 controls were used. Initially, tetra amplification refractory mutation system-PCR was used to determine the role of PSMD1 gene polymorphisms (rs1549339, rs13402242) in industrial workers and controls. Frequency of homozygous mutant genotype of rs1549339 (OR: 2.23, 95% CI: 1.51-3.32, p = 0.0001) and rs13402242 (OR: 2.96, 95% CI: 1.52-5.75, p = 0.001) was observed significantly higher in exposed individuals vs controls. Secondly, qPCR was performed for expression analysis of PSMD1 gene. Significant down-regulated expression of PSMD1 gene (p < 0.0001) was observed vs controls, and this down-regulation was observed more pronounced in smokers (p < 0.0001) with maximum exposure duration (p < 0.0008). This down-regulated expression was observed significantly more pronounced in welding (p < 0.004) and brick kiln industries (p < 0.04) compared to other selected industries. The obtained results suggest that the exposure to arsenic may have an increased risk of developing disease(s) because of arsenic-induced PSMD1 variations.

Arsenic Metabolism and Toxicity: Influence of Trace Elements

Article

Full-text available

Apr 2023

Uttam Chowdhury

The tissue and fluid samples (hair, nail, and urine) were collected from arsenic-exposed people in Bangladesh and West Bengal-India. But only the fluid samples (urine and blood) were collected from arsenic-exposed people in Mexico. Trace elements (As, Se, Zn, Co, Cu, Pb, Cd, Ni, Mn, and Hg) were analyzed in hair, nail, urine, as well as blood of arsenic exposed people by using ICP-MS, and arsenic metabolites were analyzed in urine by using HPLC-ICP-MS to know the influence of trace elements for biotransformation process of inorganic arsenic. The results of this study suggest that trace elements may have influenced the biotransformation process of inorganic arsenic in humans. The results also suggest that Se, Zn, Mn, Cu, as well as Hg, may decrease arsenic methylation and increase inorg-arsenic but decrease DMA in blood and urine, and it could be concentration dependent. We need more research on it and to find the real picture of the impact of trace elements for the methylation process of inorg-As. Can a mixture of trace elements have more impact on arsenic metabolism/toxicity compared to arsenic itself? 2022 Sciforce Publications. All rights reserved.

Assessment of Arsenic poisoning among printing textile workers in Baghdad.

Article

Oct 2017

Ali A. Ali sahib

Background: Workers of textile industry are mainly exposed to a variety of toxic dyes, bleaching agents, salts, acids, alkalis and heavy metals like arsenic through evaporation and inhale by workers or direct skin contact during the textile mordant process and possibly health effect through the printing processObjectives : to assess the health effects of mild to moderate long term exposure to Arsenic trioxide on textile printing workers and to evaluate and compare the clinical utility of blood and urine arsenic for predicting arsenic poisoning.Methods: In this historic cohort study, measurement of serum and urine levels of arsenic of 65exposed workers and 63non exposed workers was carried out during march 2014 through march 2015 All of the studies cases were worked in a cotton textile factories and considered as target population for detection of any possible industrial chronic arsenic exposure associated sign and symptoms . The non-exposed workers were randomly selected from office personnel of the same factories. Clinical examination, signs and symptoms and a questionnaire method used for analysis in both groups.Results: both groups have a similar age structure. Statistical difference was present between the serum arsenic and arsenic in urine mean values for both the exposed and non-exposed groups. The prevalence ratio for the exposure was higher than one for arsenic in urine. The best cut-off values of arsenic in urine to diagnosis arsenic poisoning based on Receiver operating characteristic curve analysis( ROC) was >90 μg/L and the areas under the curve equal to 0.98 was determined for the prediction early chronic arsenic poisoning.Conclusion: measurement of arsenic in urine in early stage was useful to detect mild to moderate health effects based on Receiver operating characteristic curve analysis (ROC) among textile printing workers exposed to arsenic.

Joint effects of per- and polyfluoroalkyl substance alternatives and heavy metals on renal health: A community-based population study in China

Article

Dec 2023

Background: Previous studies have indicated that chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs), when used as an alternative to per- and polyfluoroalkyl substances (PFASs), result in kidney toxicity. However, their co-exposure with heavy metals, has not yet been described. Objectives: To explore the joint effects of Cl-PFESAs and heavy metal exposure on renal health in Chinese adults, and identify specific pollutants driving the associations. Methods: Our sample consists of 1312 adults from a cross-sectional survey of general communities in Guangzhou, China. We measured Cl-PFESAs, legacy PFASs (perfluorooctanoic acid [PFOA] and perfluorooctane sulfonated [PFOS]), and heavy metals (arsenic, cadmium, and lead). The relationship between single pollutant and glomerular filtration rate (eGFR) and the odds ratio (OR) of chronic kidney disease (CKD) was studied using Generalized additive models (GAMs). Bayesian Kernel Machine Regression (BKMR) models were applied to assess joint effects of Cl-PFESAs and heavy metals. Additionally, we conducted a sex-specific analysis to determine the modification effect of this variable. Results: In single pollutant models, CI-PFESAs, PFOA, PFOS and arsenic were negatively associated with eGFR. Additionally, PFOA and heavy metals were positively correlated with the OR of CKD. For example, the estimated change with 95% confidence intervals (CI) of eGFR at from the highest quantile of 6:2 Cl-PFESA versus the lowest quantile was -5.65 ng/mL (95% CI: -8.21, -3.10). Sex played a role in modifying the association between 8:2 Cl-PFESA, PFOS and eGFR. In BKMR models, pollutant mixtures had a negative joint association with eGFR and a positive joint effect on CKD, especially in women. Arsenic appeared to be the primary contributing pollutant. Conclusion: We provide epidemiological evidence that Cl-PFESAs independently and jointly with heavy metals impaired kidney health. More population-based human and animal studies are needed to confirm our results.

Association of selenium, arsenic, and other trace elements in drinking water and urine in residents of the plateau region in China

Article

Full-text available

Dec 2021
ENVIRON SCI POLLUT R

Drinking water is considered to be an important exposure pathway for humans to ingest trace elements; human urine samples are widely accepted as biometric substrates that can reflect human exposure to trace elements. The current study aimed at investigating the concentrations of trace elements including selenium (Se), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn) in drinking water and human urine in plateau region of China, determining the association among trace elements in drinking water and urine, and analyzing their associations with age and gender. The results showed that the majority of trace element concentrations were in the range of the World Health Organization (WHO 2011) guideline values, in both urine samples of male and female, and the median values were descending in the order: Zn > Cu > As > Se > Cr > Ni > Mn > Pb > Cd > Co. Selenium contributed to the excretion of As, Cr, Cu, Cd, and Zn in human body, group of 31–40 years appeared to present the greatest excretion ability in most of the trace elements. Weak positive correlations were observed between age and Mn in female urine samples, and negative correlations were observed between age and Se, As, Co, and Cu in male urine samples and between age and Co in female urine samples, respectively. Significant positive correlation was observed in As between drinking water and the whole human urine. In the same family, female seemed to show higher proportions of urinary As levels than male. This study will provide elementary information regarding trace element levels in drinking water and human urine in residents in plateau region of China and is helpful to provide reference for dietary nutrient trace element intake and effective control for local resident.

Groundwater arsenic contamination in the Bengal Delta Plain is an important public health issue: A review

Article

Full-text available

Jun 2021

Open Access from DOI: https://doi.org/10.52905/hbph.v1.7 There is a close association between human biology, epidemiology and public health. Exposure to toxic elements is one area of such associations and global concerns. The Bengal Delta Plain (BDP) is a region where contamination of ground water by arsenic has assumed epidemic proportions. Apart from dermatological manifestations, chronic exposure to arsenic causes a heavy toll through several carcinogenic and non-carcinogenic disorders. This article provides a global overview of groundwater arsenic contamination in the BDP region, especially the sources, speciation, and mobility of arsenic, and critically reviews the effects of arsenic on human health. The present review also provides a summary of comprehensive knowledge on various measures required for mitigation and social consequences of the problem of arsenic contaminated groundwater in the BDP region.

Effects of storage conditions on the stability and distribution of clinical trace elements in whole blood and plasma: Application of ICP-MS

Article

Dec 2021
J TRACE ELEM MED BIO

Background Knowledge of trace element stability during sample handling and preservation is a prerequisite to produce reliable test results in clinical trace element analysis. Method An alkaline dissolution method has been developed using inductively coupled plasma mass spectrometry to quantify eighteen trace element concentrations: vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, bromine, molybdenum, cadmium, antimony, iodine, mercury, thallium, lead, and bismuth in human blood, using a small sample volume of 0.1 mL. The study evaluated the comparative effects of storage conditions on the stability of nutritionally essential and non-essential elements in human blood and plasma samples stored at three different temperatures (4 °C, −20 °C and −80 °C) over a one-year period, and analysed at multiple time points. The distribution of these elements between whole blood and plasma and their distribution relationships are illustrated using blood samples from 66 adult donors in Queensland. Results The refrigeration and freezing of blood and plasma specimens proved to be suitable storage conditions for many of the trace elements for periods up to six months, with essentially unchanged concentrations. Substantially consistent recoveries were obtained by preserving specimens at −20 °C for up to one year. Ultra-freezing of the specimens at −80 °C did not improve stability; but appeared to result in adsorption and/or precipitation of some elements, accompanied by a longer sample thawing time. A population sample study revealed significant differences between the blood and plasma concentrations of six essential elements and their relationships also varied significantly for different elements. Conclusion Blood and plasma specimens can be reliably stored at 4 °C for six months or kept frozen at −20 °C up to one year to obtain high quality test results of trace elements.

Diet and erythrocyte metal concentrations in early pregnancy—cross-sectional analysis in Project Viva

Article

May 2021

Background Dietary sources of metals are not well established among pregnant women in the United States. Objective We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy. Methods In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999–2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food–metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals’ concentrations. Results Participants’ mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (−0.55 ng/g; 95% CI: −0.82, −0.28 ng/g) and lower Hg (−2.67 ng/g; 95% CI: −3.55, −1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%–50%) and Hg (35%–70%). Conclusions Our DWAS provides a systematic evaluation of diet–metals relations. Prenatal diet may be an important source of exposures to metals.

Assessment of arsenic exposure and its mitigation intervention in severely exposed population of Buxar district of Bihar, India

Article

Full-text available

Apr 2021

Objective The present study aims to carry out the assessment of arsenic contamination in groundwater samples along with the health status of the exposed population of Buxar district of Bihar.Methods In the present study, randomly 80 groundwater samples were collected from the handpumps across the village households. For the health assessment, blood samples from human subjects were collected from the same household to know the status of the arsenic contamination in their body and were analysed.ResultsThe study showed significantly very high arsenic contamination in their handpumps as well as in the blood samples of the exposed subjects. The maximum arsenic concentration observed in the handpump water sample was 1908 μg/L, while in blood sample of an individual was 462.1 μg/L. Cancer in 12 subjects was also observed within 2 years. The mitigation intervention was carried out by installing an arsenic filter plant for this arsenic exposed village population. After one year of the usage of the installed arsenic filter, there was significant reduction in the disease symptoms in the exposed population.Conclusion The present study deciphers the groundwater status as well as the health status of the arsenic exposed population of a village of Bihar along with an mitigation approach to overcome the disease burden.

Medical geology of arsenic

Chapter

Jan 2024

Theophilus Clavell Davies

Assessing Acute and Chronic Risks of Human Exposure to Arsenic: A Cross-Sectional Study in Ethiopia Employing Body Biomarkers

Article

Full-text available

May 2024

Background:Arsenic, a widely recognized and highly toxic carcinogen, is regarded as one of the most hazardous metalloids globally. However, the precise assessment of acute and chronic human exposure to arsenic and its contributing factors remains unclear in Ethiopia. Objective:The primary goal of this study was to assess the levels of acute and chronic arsenic exposure, as well as the contributing factors, using urine and nail biomarkers. Methods:A community-based analytical cross-sectional study design was employed for this study. Agilent 7900 series inductively coupled plasma mass spectrometry was used to measure the concentrations of arsenic in urine and nail samples. We performed a multiple linear regression analysis to assess the relationships between multiple predictors and outcome variables. Results:The concentration of arsenic in the urine samples ranged from undetectable (<0.01) to 126.13, with a mean and median concentration of 16.02 and 13.5 μg/L, respectively. However, the mean and median concentration of arsenic in the nails was 1.01, ranging from undetectable (<0.01 μg/g) to 2.54 μg/g. Furthermore, Pearson’s correlation coefficient analysis showed a significant positive correlation between arsenic concentrations in urine and nail samples (r = 0.432, P < .001). Also, a positive correlation was observed between urinary (r = 0.21, P = .007) and nail (r = 0.14, P = .044) arsenic concentrations and the arsenic concentration in groundwater. Groundwater sources and smoking cigarettes were significantly associated with acute arsenic exposure. In contrast, groundwater sources, cigarette smoking, and the frequency of showers were significantly associated with chronic arsenic exposure. Conclusions:The study’s findings unveiled the widespread occurrence of both acute and chronic arsenic exposure in the study area. Consequently, it is crucial to prioritize the residents in the study area and take further measures to prevent both acute and chronic arsenic exposure.

Assessing Acute and Chronic Risks of Human Exposure to Arsenic: A Cross-Sectional Study in Ethiopia Employing Body Biomarkers

Article

Full-text available

May 2024

Background Arsenic, a widely recognized and highly toxic carcinogen, is regarded as one of the most hazardous metalloids globally. However, the precise assessment of acute and chronic human exposure to arsenic and its contributing factors remains unclear in Ethiopia. Objective The primary goal of this study was to assess the levels of acute and chronic arsenic exposure, as well as the contributing factors, using urine and nail biomarkers. Methods A community-based analytical cross-sectional study design was employed for this study. Agilent 7900 series inductively coupled plasma mass spectrometry was used to measure the concentrations of arsenic in urine and nail samples. We performed a multiple linear regression analysis to assess the relationships between multiple predictors and outcome variables. Results The concentration of arsenic in the urine samples ranged from undetectable (<0.01) to 126.13, with a mean and median concentration of 16.02 and 13.5 μg/L, respectively. However, the mean and median concentration of arsenic in the nails was 1.01, ranging from undetectable (<0.01 μg/g) to 2.54 μg/g. Furthermore, Pearson’s correlation coefficient analysis showed a significant positive correlation between arsenic concentrations in urine and nail samples (r = 0.432, P < .001). Also, a positive correlation was observed between urinary (r = 0.21, P = .007) and nail (r = 0.14, P = .044) arsenic concentrations and the arsenic concentration in groundwater. Groundwater sources and smoking cigarettes were significantly associated with acute arsenic exposure. In contrast, groundwater sources, cigarette smoking, and the frequency of showers were significantly associated with chronic arsenic exposure. Conclusions The study’s findings unveiled the widespread occurrence of both acute and chronic arsenic exposure in the study area. Consequently, it is crucial to prioritize the residents in the study area and take further measures to prevent both acute and chronic arsenic exposure.

Deciduous teeth from the New Hampshire Birth Cohort Study: Early life environmental and dietary predictors of dentin elements

Article

May 2024
ENVIRON RES

Relationship Between Arsenic in Biological Media and Breast Cancer: A Systematic Review and Meta-Analysis

Article

Full-text available

Apr 2024
BIOL TRACE ELEM RES

Arsenic (As) is an environmental pollutant with carcinogenic effects and breast cancer (BC) is a prevalent malignant tumor in women. The goal of this meta-analysis was to establish a connection between biological sample As levels and the risk of developing BC. Pub Med, Web of Science, Scopus, and Elsevier were used to systematically screen the literature published between 1990 and 2023. The Newcastle-Ottawa scale was also used in assessing the quality of publications. A random-effects model was used to assess the pertinent data that was gleaned from these articles. Using the I² index the heterogeneity of studies was performed. Egger’s test and funnel plots were used to look at publication bias. We identified 16 epidemiologic studies that included 2713 women with BC and 5347 healthy individuals. The results showed that the difference between the case group and the control group was 0.72 [95% confidence interval (CI) 0.30 to 1.14]. According to subgroup analysis, the value for blood was 0.18 [95% CI 0.01 to 0.35], whereas the value for hair was 3.08 [95% CI 0.19 to 5.97]. The present meta-analysis suggested that As levels were significantly higher in BC patients than in controls. This systematic review and meta-analysis provide evidence supporting a positive relationship between arsenic levels in biological media and BC risk. These findings highlight the importance of further research to investigate the mechanisms of this association and explore potential preventive strategies to reduce the adverse effects of arsenic exposure on BC.

Collection and handling of biomarkers of inorganic arsenic exposure in statistical analyses

Chapter

Jan 2024

Association of exposure to multiple heavy metals during pregnancy with the risk of gestational diabetes mellitus and insulin secretion phase after glucose stimulation

Article

Jan 2024
ENVIRON RES

Invited Perspective: Humanized Mice for Arsenic Metabolism—A Better Model for Investigating Arsenic-Induced Diseases?

Article

Dec 2023

Biomarker and Arsenic

Chapter

Aug 2023

Arsenic exposure may lead to severe health problems for human beings. It affects both males and females non-selectively. The primary signs of arsenic exposure include nausea, abdominal pain, vomiting, and muscular discomfort while chronic exposure may lead to raindrop pigmentation, keratosis, gastrointestinal imbalances, neurological disorder, and cancer. Raindrop pigmentation is the first sign of arsenicosis followed by hyperkeratosis. At present, hairs, nails, and urine are effective biomarkers of arsenic exposure detection while blood, hematological parameters, hormones, tumour markers, and immunological parameters may act as a biomarker for arsenic toxicity in the future. Since, the increase in level of arsenic is directly correlated with an increase in different hormone levels including metabolic hormones including T3, T4, TSH, and steroidal hormones including testosterone, estrogen, and progesterone. The rise in the level of these hormones is directly correlated with the dose and duration of arsenic exposure which showed that not only female hormone estrogen and progesterone but male hormones testosterones are also increased by an increase in arsenic levels. Arsenic is associated with RBCs and it may act as an effective biomarker in finding arsenic load in an individual. Blood arsenic is a very good biomarker to detect arsenic mobilization between different tissues. Free oxygen radicals are showing overexpression due to arsenic exposure. Levels of hydrogen peroxide, superoxide radicals, hydroxyl radicals, peroxyl radicals, and glutathione peroxidase is showing high increase in people getting arsenic exposure. The expression is directly proportional to concentration and duration of exposure which indicate that it may also act as a biomarker for detecting arsenic toxicity. Many tumour markers are increasing in arsenic-induced cancer which showed a direct correlation of these tumour markers with carcinogenesis. The level of arsenic determines the expression of these tumour markers. So, it is concluded that haematological, biochemical, hormonal, and tumour markers may work as biomarkers for future detection of arsenic among people residing in the arsenic hit areas.KeywordsArsenicBiomarkersBloodTumour

Arsenic disrupts extracellular vesicle-mediated signaling in regenerating myofibers

Article

Aug 2023
TOXICOL SCI

Chronic exposure to environmental arsenic is a public health crisis affecting hundreds of millions of individuals worldwide. Though arsenic is known to contribute to many pathologies and diseases, including cancers, cardiovascular and pulmonary diseases, and neurological impairment, the mechanisms for arsenic-promoted disease remain unresolved. This is especially true for arsenic impacts on skeletal muscle function and metabolism, despite the crucial role that skeletal muscle health plays in maintaining cardiovascular health, systemic homeostasis, and cognition. A barrier to researching this area is the challenge of interrogating muscle cell-specific effects in biologically relevant models. Ex vivo studies investigating mechanisms for muscle-specific responses to arsenic or other environmental contaminants primarily utilize traditional two-dimensional culture models that cannot elucidate effects on muscle physiology or function. Therefore, we developed a contractile three-dimensional muscle construct model-composed of primary mouse muscle progenitor cells differentiated in a hydrogel matrix-to study arsenic exposure impacts on skeletal muscle regeneration. Muscle constructs exposed to low-dose (50 nM) arsenic exhibited reduced strength and myofiber diameter following recovery from muscle injury. These effects were attributable to dysfunctional paracrine signaling mediated by extracellular vesicles (EVs) released from muscle cells. Specifically, we found that EVs collected from arsenic-exposed muscle constructs recapitulated the inhibitory effects of direct arsenic exposure on myofiber regeneration. In addition, muscle constructs treated with EVs isolated from muscles of arsenic-exposed mice displayed significantly decreased strength. Our findings highlight a novel model for muscle toxicity research and uncover a mechanism of arsenic-induced muscle dysfunction by the disruption of EV-mediated intercellular communication.

Genotoxicity and mutagenicity in blood and drinking water induced by arsenic in an impacted gold mining region in Colombia

Article

May 2023
ENVIRON RES

Arsenic (As) is one of the most dangerous substances that can affect human health and long-term exposure to As in drinking water can even cause cancer. The objective of this study was to investigate the concentrations of total As in the blood of inhabitants of a Colombian region impacted by gold mining and to evaluate its genotoxic effect through DNA damage by means of the comet assay. Additionally, the concentration of As in the water consumed by the population as well as the mutagenic activity of drinking water (n = 34) in individuals were determined by hydride generator atomic absorption spectrometry and the Ames test, respectively. In the monitoring, the study population was made up of a group of 112 people, including inhabitants of four municipalities: Guaranda, Sucre, Majagual, and San Marcos from the Mojana region as the exposed group, and Montería as a control group. The results showed DNA damage related to the presence of As in blood (p < 0.05) in the exposed population, and blood As concentrations were above the maximum allowable limit of 1 μg/L established by the ATSDR. A mutagenic activity of the drinking water was observed, and regarding the concentrations of As in water, only one sample exceeded the maximum permissible value of 10 μg/L established by the WHO. The intake of water and/or food containing As is potentially generating DNA damage in the inhabitants of the Mojana region, which requires surveillance and control by health entities to mitigate these effects.

Individual, Independent, and Joint Associations of Toxic Metals and Manganese on Hypertensive Disorders of Pregnancy: Results from the MIREC Canadian Pregnancy Cohort

Article

Apr 2023
ENVIRON HEALTH PERSP

Background: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective. Objectives: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women. Methods: Metal concentrations were analyzed in first and third trimester maternal blood (n=1,560). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures. Results: Each doubling of third trimester Pb (RR=1.54; 95% CI: 1.06, 2.22) and first trimester blood As (RR=1.25; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As (RR=3.40; 95% CI: 1.40, 8.28) and Mn (RR=0.63; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension (RR=1.31; 95% CI: 0.60, 2.85) or preeclampsia (RR=0.92; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals. Discussion: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. https://doi.org/10.1289/EHP10825.

Aberrantly Expressed Genes in HaCaT Keratinocytes Chronically Exposed to Arsenic Trioxide

Article

Full-text available

Feb 2011

Inorganic arsenic is a known environmental toxicant and carcinogen of global public health concern. Arsenic is genotoxic and cytotoxic to human keratinocytes. However, the biological pathways perturbed in keratinocytes by low chronic dose inorganic arsenic are not completely understood. The objective of the investigation was to discover the mechanism of arsenic carcinogenicity in human epidermal keratinocytes. We hypothesize that a combined strategy of DNA microarray, qRT-PCR and gene function annotation will identify aberrantly expressed genes in HaCaT keratinocyte cell line after chronic treatment with arsenic trioxide. Microarray data analysis identified 14 up-regulated genes and 21 down-regulated genes in response to arsenic trioxide. The expression of 4 up-regulated genes and 1 down-regulated gene were confirmed by qRT-PCR. The up-regulated genes were AKR1C3 (Aldo-Keto Reductase family 1, member C3), IGFL1 (Insulin Growth Factor-Like family member 1), IL1R2 (Interleukin 1 Receptor, type 2), and TNFSF18 (Tumor Necrosis Factor [ligand] SuperFamily, member 18) and down-regulated gene was RGS2 (Regulator of G-protein Signaling 2). The observed over expression of TNFSF18 (167 fold) coupled with moderate expression of IGFL1 (3.1 fold), IL1R2 (5.9 fold) and AKR1C3 (9.2 fold) with a decreased RGS2 (2.0 fold) suggests that chronic arsenic exposure could produce sustained levels of TNF with modulation by an IL-1 analogue resulting in chronic immunologic insult. A concomitant decrease in growth inhibiting gene (RGS2) and increase in AKR1C3 may contribute to chronic inflammation leading to metaplasia, which may eventually lead to carcinogenicity in the skin keratinocytes. Also, increased expression of IGFL1 may trigger cancer development and progression in HaCaT keratinocytes.

The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population

Article

Mar 2023
ENVIRON HEALTH PERSP

Background: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. Objective: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status. Methods: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms: a) PBO (n=102), b) 400μg FA/d (400FA; n=153), c) 800μg FA/d (800FA; n=151), d) 3g creatine/d (creatine; n=101), or e) 3g creatine+400μg of FA/d (creatine+400FA; n=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24. Results: At baseline, 80.3% (n=489) of participants were folate sufficient (≥9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89μg/L at baseline to 2.73±1.74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine+400FA group was greater than that of the PBO group (p=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA: -10.4 (95% CI: -11.9, -8.75), 800FA: -9.54 (95% CI: -11.1, -7.97), creatine: -5.85 (95% CI: -8.59, -3.03), creatine+400FA: -8.44 (95% CI: -9.95, -6.90), PBO: -2.02 (95% CI: -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8), creatine+400FA: 7.45 (95% CI: 5.23, 9.71), PBO: -0.15 (95% CI: -2.85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (p<0.05). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI: -3.5, -14.8)] and bDMAs [-5.9% (95% CI: -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7.16% (95% CI: -0.48, -14.3) and -3.1% (95% CI: -0.1, -6.2), respectively] for those who remained on 800FA supplementation. Conclusions: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https://doi.org/10.1289/EHP11270.

Arsenic and developmental toxicity and reproductive disorders

Chapter

Jan 2023

Facile Lego-Spinner Pretreatment Device for Analysis of Arsenic Species in Dried Blood Spots by Ion Chromatography-Inductively Coupled Plasma-Mass Spectrometry

Article

Jan 2023

Dried blood spot (DBS) detection has the advantages of small blood collection, convenience, and reliability, which provides a possibility for large-scale evaluation of arsenic exposure in human population. Herein, a facile Lego-spinner pretreatment device is rationally designed for speciation analysis of arsenic in DBSs by ion chromatography-inductively coupled plasma-mass spectrometry (IC-ICP-MS). In the mixing mode of the Lego-spinner, the magnetic stir bar in the centrifuge tube rotates under a magnetic field to assist the dispersive extraction of arsenic species in the DBS with reagents. In the centrifugation mode of the Lego-spinner, the arsenic extract is separated from the blood matrix for the subsequent IC-ICP-MS analysis. For the DBS prepared from 80 μL of whole blood, the whole pretreatment operation can be completed within 25 min. The detection limits of arsenobetaine, arsenite, dimethylarsenate, monomethylarsonate, and arsenate in the DBS are 0.09-0.15 μg L-1, and precisions are <11%. The concentrations of these five arsenic species are highly correlated between whole blood and the DBS (r2 > 0.97), and Bland-Altman analysis indicates that the concentration difference of arsenic species between whole blood and the DBS is within ±20%. The DBS sampling approach can effectively preserve arsenic species for at least 30 days at 4 °C, and the contents of arsenic species in the DBS prepared from capillary blood are in a reasonable agreement with those of venous whole blood (gold standard). This Lego-spinner provides a handy and efficient tool for fast extraction of arsenic species in DBSs, facilitating the in-depth study of arsenic migration and transformation in the human body.

Early pregnancy essential and non-essential metal mixtures and maternal antepartum and postpartum depressive symptoms

Article

Dec 2022
NEUROTOXICOLOGY

Background: Mood disorders are common during and after pregnancy, and environmental metals may contribute to increased risk. Antepartum metal exposures have not been well characterized in relation to maternal depression. We evaluated the extent to which early pregnancy erythrocyte concentrations of essential and non-essential metals were prospectively associated with antepartum and postpartum depressive symptoms. Methods: Participants were 1226 women in Project Viva, a longitudinal cohort recruited during pregnancy (1999-2002). We measured concentrations of 11 metals in maternal first trimester erythrocytes (arsenic, barium, cadmium, cesium, copper, mercury, magnesium, manganese, lead, selenium, zinc). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed elevated depressive symptoms (≥13; 0-30 scale) at mid-pregnancy and at 6 and 12 months postpartum. We applied latent class mixed modeling to identify symptom trajectories. Adjusting for maternal sociodemographics and co-exposures, we examined associations between the metal mixture and depressive symptoms using logistic (for EPDS≥13)/multinomial (for symptom trajectories) regression and quantile g-computation. Results: In this cohort of moderately high socioeconomic status participants (e.g., 72% college graduate), low-level metal concentrations were weakly to moderately correlated (Spearman: -0.24 to 0.59); the prevalence of depressive symptoms ranged from 9% (mid-pregnancy) to 6% (12 months postpartum); and three trajectories (stable low; elevated mid-pregnancy, then decreasing; moderate mid-pregnancy, then increasing) best fit the EPDS data. The early pregnancy erythrocyte metal mixture was not associated with maternal depressive symptoms in logistic, multinomial, or mixture models. For individual metals, most confidence intervals (CI) included the null. There was weak evidence that arsenic, lead, and selenium were moderately associated with elevated odds of depressive symptoms and/or trajectories. However, the odds ratios (95% CI) per doubling of these three metals were imprecise [e.g., arsenic: 1.13 (0.94, 1.40) for EPDS≥13 at six months postpartum; lead: 1.19 (0.80, 1.77) for EPDS≥13 at mid-pregnancy; selenium: 2.35 (0.84, 6.57) for elevated mid-pregnancy, then decreasing versus stable low trajectory]. Discussion: We did not observe strong, consistent evidence of associations between early pregnancy erythrocyte metal concentrations and subsequent maternal antepartum and postpartum depressive symptoms.

Melanocytotoxic chemicals and their toxic mechanisms

Article

Aug 2022

Melanocyte cell death can lead to various melanocyte-related skin diseases including vitiligo and leukoderma. Melanocytotoxic chemicals are one of the most well-known causes of nongenetic melanocyte-related diseases, which induce melanocyte cell death through apoptosis. Various chemicals used in cosmetics, medicine, industry and food additives are known to induce melanocyte cell death, which poses a significant risk to the health of consumers and industrial workers. This review summarizes recently reported melanocytotoxic chemicals and their mechanisms of toxicity in an effort to provide insight into the development of safer chemicals.

Concentrations of blood and urinary arsenic species and their characteristics in general Korean population

Article

Jul 2022
ENVIRON RES

Arsenic (As) exposure has been extensively studied by investigating As species (e.g., inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)) in urine, yet recent research suggests that blood could be a possible biomarker of As exposure. These investigations, however, were conducted on iAs-contaminated areas, and evidence on populations exposed to low levels of iAs is limited. This study aimed to describe the levels and distributions of As species in urine and blood, as well as to estimate methylation efficiency and related factors in the Korean population. Biological samples were obtained by the Korean Ministry of Food and Drug Safety. A total of 2025 urine samples and 598 blood samples were utilized in this study. Six As species were measured using ultra-high-performance liquid chromatography with inductively coupled plasma mass spectrometry (UPLC-ICP-MS): As(V), As(III), MMA, DMA, arsenobetaine (AsB), and arsenocholine (AsC). Multiple linear regression models were used to examine the relationship between As species (concentrations and proportions) and covariates. AsB was the most prevalent species in urine and blood. The relative composition of iAs, MMA, DMA, and AsC in urine and blood differed significantly. Consumption of blue-backed fish was linked to higher levels of AsB in urine and blood. Type of drinking water and multigrain rice consumption were associated with increased iAs concentration in urine. Except for iAs, every species had correlations in urine and blood in both univariate and multivariate analyses. Adolescents and smokers presented a lower methylation efficiency (higher %MMA and lower %DMA in urine) and females presented a higher methylation efficiency (lower %iAs, %MMA, and higher %DMA in urine). In conclusion, blood iAs concentration cannot represent urinary iAs; nonetheless, different compositions of urine and blood might reflect distinct information about iAs exposure. Further investigations on exposure factors and health are needed using low-exposure groups.

Levels of leachable elements from long-term use of enFlow fluid warmer

Article

Full-text available

Jul 2022

Objective In the delivery of intravenous fluids, in-line warming devices frequently transfer heat using a metal heating plate, which if uncoated can risk elution. This bench study examined extractable elements detected following long-term use of the parylene-coated enFlow ® Disposable IV/Blood Warmer. Methods We tested 16 clinically relevant challenge fluids typical of the surgical setting, including commercially available single donor blood and blood products as well as intravenous saline and electrolyte solutions. After 72 h of warming at 40°C (104°F) via the enFlow, analytical chemistry identified and quantified the most clinically significant extractable elements (arsenic, barium, cadmium, copper, and lead) to estimate chemical exposure. We also measured the extracted concentrations of these five elements following simulated use of the device with three solutions (Sterofundin ISO, Plasma-Lyte 148, and whole blood) that were pumped through the warmed device at two different flow rates (0.2 and 5.5 mL min ⁻¹ ). Results Across all scenarios of acute and long-term exposures for different populations, the enFlow demonstrated low toxicological risks as measured by the calculation of tolerable exposure for extracted arsenic, barium, cadmium, copper, and lead. Conclusion The results suggest biological safety for the use of parylene-coated enFlow with a variety of intravenous solutions and in different therapeutic scenarios.

Trivalent arsenic impairs the effector response of human CD4+ and CD8+ T cells to influenza A virus ex vivo

Article

May 2022
FOOD CHEM TOXICOL

Arsenic is a persistent environmental contaminant that humans are exposed to primarily through contaminated water supplies. Arsenic has been shown to have numerous immunomodulatory effects, including deleterious effects on T cell function. However, the effect of arsenic on human T cell function in the context of influenza infection remains poorly characterized. The goal of this study was to determine the effects of arsenic on T cell activation and effector function in a human-relevant ex vivo model with influenza challenge. Flow cytometric analysis of T cells following the treatment of primary human peripheral blood mononuclear cells with environmentally relevant concentrations of arsenic trioxide and subsequent challenge with influenza A virus showed reduced viability, alterations in activation, a reduction in the population of memory cells, and reduced effector function evidenced by IFNγ and granzyme B production. Overall, these studies suggest that arsenic impairs the human T cell response to influenza which corroborates epidemiological findings and could have further implications for antiviral immunity and vaccine efficacy.

Urine Dilution Correction Methods Utilizing Urine Creatinine or Specific Gravity in Arsenic Analyses: Comparisons to Blood and Water Arsenic in the FACT and FOX Studies in Bangladesh

Article

Full-text available

May 2022

Urinary As (uAs) is a biomarker of As exposure. Urinary creatinine (uCr) or specific gravity (SG) are used to correct uAs for urine dilution. However, uCr is correlated with As methylation, whereas SG has limitations in individuals with kidney damage. We aimed to evaluate which urine dilution correction methods for uAs most accurately predicted blood As (bAs). We used data from the Folic Acid and Creatine Trial (FACT; N = 541) and Folate and Oxidative Stress (FOX; N = 343) study in Bangladesh. Three linear regression models were assessed using uAs (1) adjusted for uCr or SG as separate covariates, (2) standardized for uCr or SG, i.e., uAs/uCr, and (3) adjusted for residual corrected uCr or SG following adjustment for age, sex and BMI. Median uAs/bAs for FACT and FOX were 114/8.4 and 140/12.3 µg/L. In FACT, two-fold increases in uAs adjusted for uCr or SG were related to 34% and 22% increases in bAs, respectively, with similar patterns in FOX. Across methods, models with uCr consistently had lower AIC values than SG. The uAs associations with bAs were stronger after adjustment for uCr vs. SG. Decisions regarding urine dilution methods should consider whether the study outcomes are influenced by factors such as methylation or medical conditions.

Effects of prenatal exposure to arsenic on neonatal birth size in Wujiang, China

Article

Mar 2022
CHEMOSPHERE

To investigate prenatal exposure to arsenic and its effect on birth size, we conducted a cross-sectional study in Wujiang City, Jiangsu, China, from June 2009 to June 2010. A total of 1722 mother-infant pairs were included in the study. A questionnaire was administered to the pregnant women and umbilical cord blood(UCB) samples were collected. Arsenic concentration in UCB was detected by inductively coupled plasma emission mass spectroscopy (ICP-MS). The birth size included birth weight, birth body length and head circumference of the newborns. The effects of arsenic exposure on birth size were assessed by multiple linear regression analysis. Arsenic concentrations in UCB ranged from 0.11 to 30.36 μg/L, the median was 1.71 μg/L. In this range of exposure, arsenic concentration was significantly negatively associated with birth weight, especially among male infants. Our results showed that prenatal exposure to arsenic level was low in Wujiang City, China. However, low prenatal arsenic exposure could have negative effects on birth weight. Our research provided evidence for the adverse effects of prenatal low-level arsenic exposure on the intrauterine growth of the fetus.

A high-throughput assay for screening the abilities of per- and polyfluoroalkyl substances in inducing plasma kallikrein-like activity

Article

Apr 2022
ECOTOX ENVIRON SAFE

The plasma consists of multiple functional serine zymogens, such as plasma kallikrein-kinin system (KKS), which are vulnerable to exogenous chemical exposure, and may closely relate to the deleterious effects. Testing whether the anthropogenic chemicals could increase the kallikrein-like activity in plasma or not would be of great help to understand their potentials in triggering the cascade activation of the plasma zymogens and explain the corresponding hematotoxicity. In this study, a novel high-throughput ex vivo assay was established to screen the abilities of emerging chemicals like per- and polyfluoroalkyl substances (PFASs) in inducing kallikrein-like activities on basis of using rat plasma as the protease zymogen source. Upon the optimization of the conditions in the test system, the assay gave sensitive fluorescent response to the stimulation of the positive control, dextran sulfate, and the dose-response showed a typical S-shaped curve with EC50 of 0.24 mg/L. The intra-plate and inter-plate relative standard deviations (RSDs) were less than 10% in the quantitative range of dextran sulfate, indicating a good reliability and repeatability of this newly-established assay. Using this method, several alternatives or congeners of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), including 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA), Ag-PFOA, K-PFOA, Na-PFOA and ammonium pentadecafluorooctanoate (APFO), were further screened, and their capabilities in inducing kallikrein-like activities were identified. The ex vivo assay newly-developed in the present study would be promising in high-throughput screening of the hematological effects of emerging chemicals of concern.

Validation of blood arsenic and manganese assessment from archived clotted erythrocyte fraction in an urban cohort of mother-child dyads

Article

Dec 2021
SCI TOTAL ENVIRON

Exposure to arsenic (As) and manganese (Mn) from contaminated food, drinking water and dust are linked to a host of adverse health effects. The recent discovery of unmonitored community exposures to hazardous levels of metals, as seen in the Flint Water Crisis and East Chicago, have demonstrated a need for novel biomonitoring methods utilizing samples other than whole blood. Here, we present a method utilizing clotted erythrocyte fraction samples, a blood component commonly archived in biorepositories, to predict whole blood levels of As and Mn. This method would allow for innovative retrospective assessments of environmental exposures in previously unused samples. Whole blood and clotted erythrocyte fraction samples were simultaneously collected from 84 participants in the Airborne Exposure to Semivolatile Organic Pollutants (AESOP) cohort study of mother-child dyads in East Chicago. Clotted erythrocyte fraction samples were prepared by alkaline dilution and subsequently analyzed using inductively coupled plasma-mass spectrometry. A strong linear relationship was observed between whole blood and clotted erythrocyte fraction with Pearson correlation coefficients (r, p < 0.001) of 0.74, and 0.82 for As and Mn, respectively. Modeled whole blood Mn levels predicted from clotted erythrocyte fractions evaluated at a test threshold representing the NHANES median of 9.7 μg/L, were found to have diagnostic sensitivity of 88% and specificity of 71%. Clotted erythrocyte partitioning of As was tested on a wide range of oral gavage doses using a rat model. Results from this investigation demonstrate clotted erythrocyte fraction samples are a viable alternative biological sample for retrospective public health surveillance of environmental exposure to As and Mn.

Provision of folic acid for reducing arsenic toxicity in arsenic‐exposed children and adults

Article

Oct 2021

Background: Arsenic is a common environmental toxin. Exposure to arsenic (particularly its inorganic form) through contaminated food and drinking water is an important public health burden worldwide, and is associated with increased risk of neurotoxicity, congenital anomalies, cancer, and adverse neurodevelopment in children. Arsenic is excreted following methylation reactions, which are mediated by folate. Provision of folate through folic acid supplements could facilitate arsenic methylation and excretion, thereby reducing arsenic toxicity. Objectives: To assess the effects of provision of folic acid (through fortified foods or supplements), alone or in combination with other nutrients, in lessening the burden of arsenic-related health outcomes and reducing arsenic toxicity in arsenic-exposed populations. Search methods: In September 2020, we searched CENTRAL, MEDLINE, Embase, 10 other international databases, nine regional databases, and two trials registers. Selection criteria: Randomised controlled trials (RCTs) and quasi-RCTs comparing the provision of folic acid (at any dose or duration), alone or in combination with other nutrients or nutrient supplements, with no intervention, placebo, unfortified food, or the same nutrient or supplements without folic acid, in arsenic-exposed populations of all ages and genders. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We included two RCTs with 822 adults exposed to arsenic-contaminated drinking water in Bangladesh. The RCTs compared 400 µg/d (FA400) or 800 µg/d (FA800) folic acid supplements, given for 12 or 24 weeks, with placebo. One RCT, a multi-armed trial, compared FA400 plus creatine (3 g/d) to creatine alone. We judged both RCTs at low risk of bias in all domains. Due to differences in co-intervention, arsenic exposure, and participants' nutritional status, we could not conduct meta-analyses, and therefore, provide a narrative description of the data. Neither RCT reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies. Folic acid supplements alone versus placebo Blood arsenic. In arsenic-exposed individuals, FA likely reduces blood arsenic concentrations compared to placebo (2 studies, 536 participants; moderate-certainty evidence). For folate-deficient and folate-replete participants who received arsenic-removal water filters as a co-intervention, FA800 reduced blood arsenic levels more than placebo (percentage change (%change) in geometric mean (GM) FA800 -17.8%, 95% confidence intervals (CI) -25.0 to -9.8; placebo GM -9.5%, 95% CI -16.5 to -1.8; 1 study, 406 participants). In one study with 130 participants with low baseline plasma folate, FA400 reduced total blood arsenic (%change FA400 mean (M) -13.62%, standard error (SE) ± 2.87; placebo M -2.49%, SE ± 3.25), and monomethylarsonic acid (MMA) concentrations (%change FA400 M -22.24%, SE ± 2.86; placebo M -1.24%, SE ± 3.59) more than placebo. Inorganic arsenic (InAs) concentrations reduced in both groups (%change FA400 M -18.54%, SE ± 3.60; placebo M -10.61%, SE ± 3.38). There was little to no change in dimethylarsinic acid (DMA) in either group. Urinary arsenic. In arsenic-exposed individuals, FA likely reduces the proportion of total urinary arsenic excreted as InAs (%InAs) and MMA (%MMA) and increases the proportion excreted as DMA (%DMA) to a greater extent than placebo (2 studies, 546 participants; moderate-certainty evidence), suggesting that FA enhances arsenic methylation. In a mixed folate-deficient and folate-replete population (1 study, 352 participants) receiving arsenic-removal water filters as a co-intervention, groups receiving FA had a greater decrease in %InAs (within-person change FA400 M -0.09%, 95% CI -0.17 to -0.01; FA800 M -0.14%, 95% CI -0.21 to -0.06; placebo M 0.05%, 95% CI 0.00 to 0.10), a greater decrease in %MMA (within-person change FA400 M -1.80%, 95% CI -2.53 to -1.07; FA800 M -2.60%, 95% CI -3.35 to -1.85; placebo M 0.15%, 95% CI -0.37 to 0.68), and a greater increase in %DMA (within-person change FA400 M 3.25%, 95% CI 1.81 to 4.68; FA800 M 4.57%, 95% CI 3.20 to 5.95; placebo M -1.17%, 95% CI -2.18 to -0.17), compared to placebo. In 194 participants with low baseline plasma folate, FA reduced %InAs (%change FA400 M -0.31%, SE ± 0.04; placebo M -0.13%, SE ± 0.04) and %MMA (%change FA400 M -2.6%, SE ± 0.37; placebo M -0.71%, SE ± 0.43), and increased %DMA (%change FA400 M 5.9%, SE ± 0.82; placebo M 2.14%, SE ± 0.71), more than placebo. Plasma homocysteine: In arsenic-exposed individuals, FA400 likely reduces homocysteine concentrations to a greater extent than placebo (2 studies, 448 participants; moderate-certainty evidence), in the mixed folate-deficient and folate-replete population receiving arsenic-removal water filters as a co-intervention (%change in GM FA400 -23.4%, 95% CI -27.1 to -19.5; placebo -1.3%, 95% CI -5.3 to 3.1; 1 study, 254 participants), and participants with low baseline plasma folate (within-person change FA400 M -3.06 µmol/L, SE ± 3.51; placebo M -0.05 µmol/L, SE ± 4.31; 1 study, 194 participants). FA supplements plus other nutrient supplements versus nutrient supplements alone In arsenic-exposed individuals who received arsenic-removal water filters as a co-intervention, FA400 plus creatine may reduce blood arsenic concentrations more than creatine alone (%change in GM FA400 + creatine -14%, 95% CI -22.2 to -5.0; creatine -7.0%, 95% CI -14.8 to 1.5; 1 study, 204 participants; low-certainty evidence); may not change urinary arsenic methylation indices (FA400 + creatine: %InAs M 13.2%, SE ± 7.0; %MMA M 10.8, SE ± 4.1; %DMA M 76, SE ± 7.8; creatine: %InAs M 14.8, SE ± 5.5; %MMA M 12.8, SE ± 4.0; %DMA M 72.4, SE ±7.6; 1 study, 190 participants; low-certainty evidence); and may reduce homocysteine concentrations to a greater extent (%change in GM FA400 + creatinine -21%, 95% CI -25.2 to -16.4; creatine -4.3%, 95% CI -9.0 to 0.7; 1 study, 204 participants; low-certainty evidence) than creatine alone. Authors' conclusions: There is moderate-certainty evidence that FA supplements may benefit blood arsenic concentration, urinary arsenic methylation profiles, and plasma homocysteine concentration versus placebo. There is low-certainty evidence that FA supplements plus other nutrients may benefit blood arsenic and plasma homocysteine concentrations versus nutrients alone. No studies reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies. Given the limited number of RCTs, more studies conducted in diverse settings are needed to assess the effects of FA on arsenic-related health outcomes and arsenic toxicity in arsenic-exposed adults and children.

Arsenic contamination in water resources and its health risk assessment

Chapter

Jan 2021

Arsenic (As) pollution of groundwater in various parts of the world is a result of natural and anthropogenic sources, prompting adverse impacts on human beings and the ecosystem and have been accounted for as one of the world’s greatest characteristic groundwater calamities to humankind. In spite of various remedial and prudent steps, the spread of As pollution in groundwater is developing and newer zones were added to the rundown of debased zone. The problem settling issues along these lines, appeared to be halfway and insufficient, which should be fortified by vital logical support. Headway in the comprehension of geochemical and assembly forms, contriving acceptable As expulsion channels, identification of deficiencies in activity and support of As evacuation strategies, outline of hazard free further springs as a substitute wellspring of groundwater, creating surfacewater-based supply plots in numerous As influenced regions, which could help in prompting relief and remediation of the issues developing out of As threat. This chapter audits the As contamination in water resources and its related health risk assessment.

Arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain area, Inner Mongolia, China

Article

Full-text available

Jun 2001

An investigation was carried out on arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain of Inner Mongolia Autonomous Region, China. Based on the screening of water samples from 96 randomly selected wells in this Region, two areas (Wuyuan and Alashan) were chosen as highly contaminated areas because arsenic in the water samples was higher than 50 g/l. Arsenic was measured using an arsenic silver diethyl dithiocarbamate method for 326 water samples from all the wells in these areas. The results show arsenic contaminated groundwater from tubuletype wells of depths about 15–30 m was serious compared with open-type wells where depth is about 3–5 m. In the Wuyuan area, 96.2% of water samples from tubule-type wells contained arsenic above 50 g/l and 69.3% in Alashan area; the highest value was 1354 g/l and 1088 g/l, respectively. In these two areas, a health survey was carried out for arsenical dermatosis. The results show the prevalence of arsenical dermatosis in the Wuyuan area was 44.8%, higher than 37.1% prevalence of arsenical dermatosis in the Alashan area. The prevalence of arsenical dermatosis was highest in the over 40yearold age group. There was no sex difference in the prevalence. Further investigation is needed to clarify the actual situation of arsenic pollution of groundwater in Inner Mongolia, China in order to reduce the adverse health effect among residents exposed to arsenic.

Toxicology : the basic science of poisons / Casarett and Doull

Article

Full-text available

Incluye bibliografía e índice

Excretion of Arsenic in Urine as a Function of Exposure to Arsenic in Drinking Water

Article

Full-text available

Sep 1999

Urinary arsenic (As) concentrations were evaluated as a biomarker of exposure in a U.S. population chronically exposed to inorganic As (InAs) in their drinking water. Ninety-six individuals who consumed drinking water with As concentrations of 8-620 microg/L provided first morning urine voids for up to 5 consecutive days. The study population was 56% male, and 44% was younger than 18 years of age. On one day of the study period, all voided urines were collected over a 24-hr period. Arsenic intake from drinking water was estimated from daily food diaries. Comparison between the concentration of As in individual urine voids with that in the 24-hr urine collection indicated that the concentration of As in urine was stable throughout the day. Comparison of the concentration of As in each first morning urine void over the 5-day study period indicated that there was little day-to-day variation in the concentration of As in urine. The concentration of As in drinking water was a better predictor of the concentration of As in urine than was the estimated intake of As from drinking water. The concentration of As in urine did not vary by gender. An age-dependent difference in the concentration of As in urine may be attributed to the higher As dosage rate per unit body weight in children than in adults. These findings suggest that the analysis of a small number of urine samples may be adequate to estimate an individual's exposure to InAs from drinking water and that the determination of the concentration of InAs in a drinking water supply may be a useful surrogate for estimating exposure to this metalloid. Images Figure 1 Figure 2 Figure 3 Figure 4

Relations between exposure to arsenic, skin lesions, and glucosuria

Article

Full-text available

May 1999

Exposure to arsenic causes keratosis, hyperpigmentation, and hypopigmentation and seemingly also diabetes mellitus, at least in subjects with skin lesions. Here we evaluate the relations of arsenical skin lesions and glucosuria as a proxy for diabetes mellitus. Through existing measurements of arsenic in drinking water in Bangladesh, wells with and without arsenic contamination were identified. Based on a questionnaire, 1595 subjects > or = 30 years of age were interviewed; 1481 had a history of drinking water contaminated with arsenic whereas 114 had not. Time weighted mean arsenic concentrations and mg-years/l of exposure to arsenic were estimated based on the history of consumption of well water and current arsenic concentrations. Urine samples from the study subjects were tested by means of a glucometric strip. People with positive tests were considered to be cases of glucosuria. A total of 430 (29%) of the exposed people were found to have skin lesions. Corresponding to drinking water with < 0.5, 0.5-1.0, and > 1.0 mg/l of arsenic, and with the 114 unexposed subjects as the reference, the prevalence ratios for glucosuria, as adjusted for age and sex, were 0.8, 1.4, and 1.4 for those without skin lesions, and 1.1, 2.2, and 2.6 for those with skin lesions. Taking exposure as < 1.0, 1.0-5.0, > 5.0-10.0 and > 10.0 mg-years/l of exposure to arsenic the prevalence ratios, similarly adjusted, were 0.4, 0.9, 1.2, and 1.7 for those without and 0.8, 1.7, 2.1, and 2.9 for those with skin lesions. All series of risk estimates were significant for trend, (p < 0.01). The results suggest that skin lesions and diabetes mellitus, as here indicated by glucosuria, are largely independent effects of exposure to arsenic although glucosuria had some tendency to be associated with skin lesions. Importantly, however, glucosuria (diabetes mellitus) may occur independently of skin lesions.

The Relationship of Arsenic Levels in Drinking Water and the Prevalence Rate of Skin Lesions in Bangladesh

Article

Full-text available

Sep 1999

To determine the relationship of arsenic-associated skin lesions and degree of arsenic exposure, a cross-sectional study was conducted in Bangladesh, where a large part of the population is exposed through drinking water. Four villages in Bangladesh were identified as mainly dependent on wells contaminated with arsenic. We interviewed and examined 1,481 subjects [Greater/equal to] 30 years of age in these villages. A total of 430 subjects had skin lesions (keratosis, hyperpigmentation, or hypopigmentation). Individual exposure assessment could only be estimated by present levels and in terms of a dose index, i.e., arsenic levels divided by individual body weight. Arsenic water concentrations ranged from 10 to 2,040 microg/L, and the crude overall prevalence rate for skin lesions was 29/100. After age adjustment to the world population the prevalence rate was 30. 1/100 and 26.5/100 for males and females, respectively. There was a significant trend for the prevalence rate both in relation to exposure levels and to dose index (p < 0.05), regardless of sex. This study shows a higher prevalence rate of arsenic skin lesions in males than females, with clear dose-response relationship. The overall high prevalence rate in the studied villages is an alarming sign of arsenic exposure and requires an urgent remedy.

Measurement of Low Levels of Arsenic Exposure: A Comparison of Water and Toenail Concentrations

Article

Full-text available

Jul 2000
AM J EPIDEMIOL

A study was conducted to evaluate toenail arsenic concentrations as a biologic marker of drinking water arsenic exposure. Study subjects were controls in a US population-based case-control study of nonmelanoma skin cancer, randomly selected from drivers' license records (those < 65 years of age) and Medicare enrollment files (those > or = 65 years of age). Between 1994 and 1997, a total of 540 controls were interviewed and toenail samples of sufficient weight were collected from 506 (93.7%) of these. Beginning in 1995, a sample of tap water was taken from the participants' homes; a total of 217 (98.6%) water samples were obtained from the 220 subjects interviewed. Arsenic determinations were made from toenail samples using neutron activation analysis. Water samples were analyzed using hydride-generation magnet sector inductively coupled mass spectrometry. Among 208 subjects with both toenail and water measurements, the correlation (r) between water and nail arsenic was 0.65 (p < 0.001) among those with water arsenic concentrations of 1 microg/liter or higher and 0.08 (p = 0.31) among those with concentrations below 1 microg/liter (overall r = 0.46, p < 0.001). Our data suggest that toenail samples provide a useful biologic marker for quantifying low-level arsenic exposure.

Smith, A.H., Lingas, E.O. & Rahman, M. Contamination of Drinking Water by Arsenic in Bangladesh: A Public Health Emergency. Bulletin of the World Health Organization 78: 1093-1103

Article

Full-text available

Feb 2000
B WORLD HEALTH ORGAN

The contamination of groundwater by arsenic in Bangladesh is the largest poisoning of a population in history, with millions of people exposed. This paper describes the history of the discovery of arsenic in drinking-water in Bangladesh and recommends intervention strategies. Tube-wells were installed to provide "pure water" to prevent morbidity and mortality from gastrointestinal disease. The water from the millions of tube-wells that were installed was not tested for arsenic contamination. Studies in other countries where the population has had long-term exposure to arsenic in groundwater indicate that 1 in 10 people who drink water containing 500 micrograms of arsenic per litre may ultimately die from cancers caused by arsenic, including lung, bladder and skin cancers. The rapid allocation of funding and prompt expansion of current interventions to address this contamination should be facilitated. The fundamental intervention is the identification and provision of arsenic-free drinking water. Arsenic is rapidly excreted in urine, and for early or mild cases, no specific treatment is required. Community education and participation are essential to ensure that interventions are successful; these should be coupled with follow-up monitoring to confirm that exposure has ended. Taken together with the discovery of arsenic in groundwater in other countries, the experience in Bangladesh shows that groundwater sources throughout the world that are used for drinking-water should be tested for arsenic.

Association of Blood Arsenic Levels with Increased Reactive Oxidants and Decreased Antioxidant Capacity in a Human Population of Northeastern Taiwan

Article

Full-text available

Nov 2001

Arsenic is a notorious environmental toxicant known as both a carcinogen and an atherogen in human beings, but the pathogenic mechanisms are not completely understood. In cell culture studies, trivalent arsenic enhanced oxidative stress in a variety of mammalian cells, and this association may be closely associated with the development of arsenic-related diseases. To investigate the effect of arsenic exposure on oxidative stress in humans, we conducted a population study to determine the relationships of blood arsenic to reactive oxidants and antioxidant capacity at the individual level. We recruited 64 study subjects ages 42-75 years from residents of the Lanyang Basin on the northeast coast of Taiwan, where arsenic content in well water varies from 0 to > or = 3,000 microg/L. We used a chemiluminescence method, with lucigenin as an amplifier for measuring superoxide, to measure the plasma level of reactive oxidants. We used the azino-diethyl-benzthiazoline sulphate method to determine the antioxidant capacity level in plasma of each study subject. We determined arsenic concentration in whole blood by hydride formation with an atomic absorption spectrophotometer. The average arsenic concentration in whole blood of study subjects was 9.60 +/- 9.96 microg/L (+/- SD) with a range from 0 to 46.50 microg/L. The level of arsenic concentration in whole blood of study subjects showed a positive association with the level of reactive oxidants in plasma (r = +0.41, p = 0.001) and an inverse relationship with the level of plasma antioxidant capacity (r = -0.30, p = 0.014). However, we found no significant association (p = 0.266) between levels of plasma reactive oxidants and antioxidant capacity. Our results also show that the lower the primary arsenic methylation capability, the lower the level of plasma antioxidant capacity (p = 0.029). These results suggest that ingestion of arsenic-contaminated well water may cause deleterious effects by increasing the level of reactive oxidants and decreasing the level of antioxidant capacity in plasma of individuals. Persistent oxidative stress in peripheral blood may be a mechanism underlying the carcinogenesis and atherosclerosis induced by long-term arsenic exposure.

Promotion of well-switching to mitigate the arsenic crisis in Bangladesh

Article

Full-text available

Feb 2002
B WORLD HEALTH ORGAN

To survey tube wells and households in Araihazar upazila, Bangladesh, to set the stage for a long-term epidemiological study of the consequences of chronic arsenic exposure. Water samples and household data were collected over a period of 4 months in 2000 from 4997 contiguous tube wells serving a population of 55000, the position of each well being determined to within +/- 30 m using Global Positioning System receivers. Arsenic concentrations were determined by graphite-furnace atomic-absorption spectrometry. In addition, groundwater samples collected every 2 weeks for an entire year from six tube wells were analysed for arsenic by high-resolution inductively coupled plasma-mass spectrometry. Half of the wells surveyed in Araihazar had been installed in the previous 5 years; 94% were privately owned. Only about 48% of the surveyed wells supplied water with an arsenic content below 50 micro g/l, the current Bangladesh standard for drinking-water. Similar to other regions of Bangladesh and West Bengal, India, the distribution of arsenic in Araihazar is spatially highly variable (range: 5-860 micro g/l) and therefore difficult to predict. Because of this variability, however, close to 90% of the inhabitants live within 100 m of a safe well. Monitoring of six tube wells currently meeting the 50 micro g/l standard showed no indication of a seasonal cycle in arsenic concentrations coupled to the hydrological cycle. This suggests that well-switching is a viable option in Araihazar, at least for the short term. Well-switching should be more systematically encouraged in Araihazar and many other parts of Bangladesh and West Bengal, India. Social barriers to well-switching need to be better understood and, if possible, overcome.

Gene Expression of Inflammatory Molecules in Circulating Lymphocytes from Arsenic-Exposed Human Subjects

Article

Full-text available

Sep 2003

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0-4.32 microg/L), intermediate (4.64-9.00 microg/L), and high (9.60-46.5 microg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncogene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagenase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease.

Rapid multi-element analysis of groundwater by high-resolution inductively coupled plasma mass spectrometry

Article

Full-text available

Jul 2004

A rapid and sensitive method was developed to determine, with a single dilution, the concentration of 33 major and trace elements (Na, Mg, Si, K, Ca, Li, Al, P, S, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Sr, Mo, Cd, In, Sn, Sb, Cs, Ba, Re, Hg, Pb, Bi, U) in groundwater. The method relies on high-resolution inductively coupled plasma mass spectrometry (HR ICP-MS) and works across nine orders of magnitude of concentrations. For most elements, detection limits for this method are considerably lower than methods based on quadrupole ICP-MS. Precision was within or close to +/-3% (1 sigma) for all elements analyzed, with the exception of Se (+/-10%) and Al (+/-6%). The usefulness of the method is demonstrated with a set of 629 groundwater samples collected from tube wells in Bangladesh (Northeast Araiharzar). The results show that a majority of tube well samples in this area exceed the WHO guideline for As of 10 microg L(-1), and that those As-safe wells frequently do not meet the guideline for Mn of 500 microg L(-1) and U of 2 microg L(-1).

Cancer Burden From Arsenic in Drinking Water in Bangladesh

Article

Full-text available

Jun 2004

We assessed the potential burden of internal cancers due to arsenic exposure in Bangladesh. We estimated excess lifetime risks of death from liver, bladder, and lung cancers using an exposure distribution, death probabilities, and cancer mortality rates from Bangladesh and dose-specific relative risk estimates from Taiwan. Results indicated at least a doubling of lifetime mortality risk from liver, bladder, and lung cancers (229.6 vs 103.5 per 100 000 population) in Bangladesh owing to arsenic in drinking water.

Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL. Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements

Article

Full-text available

Mar 2005

Biologic monitoring (i.e., biomonitoring) is used to assess human exposures to environmental and workplace chemicals. Urinary biomonitoring data typically are adjusted to a constant creatinine concentration to correct for variable dilutions among spot samples. Traditionally, this approach has been used in population groups without much diversity. The inclusion of multiple demographic groups in studies using biomonitoring for exposure assessment has increased the variability in the urinary creatinine levels in these study populations. Our objectives were to document the normal range of urinary creatinine concentrations among various demographic groups, evaluate the impact that variations in creatinine concentrations can have on classifying exposure status of individuals in epidemiologic studies, and recommend an approach using multiple regression to adjust for variations in creatinine in multivariate analyses. We performed a weighted multivariate analysis of urinary creatinine concentrations in 22,245 participants of the Third National Health and Nutrition Examination Survey (1988-1994) and established reference ranges (10th-90th percentiles) for each demographic and age category. Significant predictors of urinary creatinine concentration included age group, sex, race/ethnicity, body mass index, and fat-free mass. Time of day that urine samples were collected made a small but statistically significant difference in creatinine concentrations. For an individual, the creatinine-adjusted concentration of an analyte should be compared with a "reference" range derived from persons in a similar demographic group (e.g., children with children, adults with adults). For multiple regression analysis of population groups, we recommend that the analyte concentration (unadjusted for creatinine) should be included in the analysis with urinary creatinine added as a separate independent variable. This approach allows the urinary analyte concentration to be appropriately adjusted for urinary creatinine and the statistical significance of other variables in the model to be independent of effects of creatinine concentration.

Urinary Creatinine and Arsenic Metabolism

Article

Full-text available

Aug 2005

Urinary creatinine is almost universally employed to adjust concentrations of urinary analytes for variations in hydration status. In the February 2005 issue of EHP, Barr et al. used data from the Third National Health and Nutrition Examination Survey (NHANES III) to establish reference ranges for urinary creatinine for specific age and demographic categories (Barr et al. 2005). They reported that the significant predictors of urinary creatinine concentrations include age, sex, race/ethnicity, body mass index, and fat-free mass. Although these indicators have been known for many years, the unintentional adjustment for these covariates when urinary metabolites are expressed per gram creatinine can have profound effects on the interpretation of data. The fact that these effects are often under-appreciated or even unnoticed renders this paper highly relevant to exposure assessment and well worth revisiting. In our studies of arsenic methylation and one-carbon metabolism, we have noted several additional complications when expressing urinary arsenic as micrograms per gram creatinine. Note that one-carbon metabolism refers to the folate-dependent biochemical pathway responsible for methylation of DNA, arsenic, and hundreds of other substrates. Our study in Bangladesh on 1,650 adults revealed that urinary creatinine concentrations are significantly correlated with plasma folate concentrations—particularly among males, who had a higher prevalence of folate deficiency than females in Bangladesh (Gamble et al. 2005). Although this association had not been previously reported, it is not surprising considering that the formation of creatine from methylation of guanidino-acetate accounts for approximately 75% of all folate-dependent transmethylation reactions (Mudd and Poole 1975) and that creatine is the direct precursor of creatinine. In some analyses, adjusting urinary arsenic for creatinine obscured correlations between folate and arsenic metabolism. In other analyses, correlations between folate and arsenic/creatinine were due in part to the associations between folate and creatinine. Correct interpretation of the data would not be possible without considering the impact of the correlation between urinary creatinine and plasma folate. As did Barr et al. (2005), we decided to include urinary creatinine in the statistical models as a separate independent variable. However, because of the intimate link between creatine metabolism and one-carbon metabolism, inclusion of urinary creatinine in some models resulted in overcontrolling for the effects of folate and homocysteine, our variables of interest. Thus, expression of total urinary arsenic per gram creatinine runs the risk of confounding relationships between total urinary arsenic and arsenic metabolism. Adjusting for the specific gravity of urine was not useful because it is so highly correlated with urinary creatinine. In summary, we concur with Barr et al. (2005) that urinary creatinine should be included in multiple regression models as a separate independent variable; in addition, the role of one-carbon metabolism as a predictor of urinary creatinine should also be considered in interpreting results. Specifically, we routinely test if urinary creatinine itself is a predictor of the outcomes of interest.

Human nails as a biomarker of arsenic exposure from well water in Inner Mongolia: Comparing atomic fluorescence spectrometry and neutron activation analysis

Article

Full-text available

Mar 2005

Arsenic (As) is found naturally in the geological strata within the Ba Men Region of Inner Mongolia, China. A study was conducted to compare the total As measurements from two analytical techniques: instrumental neutron activation analysis (INAA) and atomic fluorescence spectrometry (AFS), and to verify nails as an exposure biomarker in this population. In 1999, nail and water samples were collected in a pilot study. Fingernails and toenails were pooled from 32 participants and analysed for total As by both INAA and AFS. Mean nail As values were 14.8+/-2.4 and 19.4+/-2.8 microg g-1 (+/-SEM) for INAA and AFS, respectively. Results from these two methods were significantly correlated (r=0.93, p<0.0001). In 2000, a second study was conducted and INAA was used to measure total As in toenails from 314 Ba Men residents. Well water samples were collected from 121 households and analysed by AFS. A significant correlation was observed between toenail and well water As (r=0.84, p<0.0001). Based on the results, INAA was significantly correlated with AFS and proved to be a reliable measure of nail As levels. In this population, toenail samples are a useful internal As exposure biomarker from drinking water sources.

Health Effects of Arsenic Longitudinal Study (HEALS): Description of a multidisciplinary epidemiologic investigation

Article

Full-text available

Apr 2006

Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes, including premalignant and malignant skin tumors, total mortality, pregnancy outcomes, and children's cognitive development. In this paper, we provide descriptions of the study methods including study design, study population, data collection, response rates, and exposure and outcome assessments. We also present characteristics of the study participants including the distribution of exposure and the prevalence of skin lesion at baseline recruitment. A total of 11,746 married men and women between 18 and 75 years of age participated in the study at baseline (a response rate of 98%) and completed a full questionnaire interview that included a food frequency questionnaire, with a response rate of 98%. Among the 98% of the participants who completed the clinical evaluation, over 90% provided blood samples and spot urine samples. Higher educational status, male gender, and presence of premalignant skin lesions were associated with an increased likelihood of providing blood and urine samples. Older participants were less likely to donate a blood sample. About one-third of the participants consumed water from a well with As concentration in each of three groups: >100 microg/l, 25-100 microg/l, and <25 microg/l. Average urinary As concentrations were 140 and 136 microg/l for males and females, respectively. HEALS has several unique features, including a prospective study design, comprehensive assessments of both past and future changes in As exposure at the individual level, a large repository of biological samples, and a full dose range of As exposures in the study population. HEALS is a valuable resource for examining novel research questions on the health effects of As exposure.

Folate, Homocysteine, and Arsenic Metabolism in Arsenic-Exposed Individuals in Bangladesh

Article

Full-text available

Dec 2005

Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = -0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = -0.45 for males, p < 0.0001; -0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.

Prevalence of Arsenic Exposure from Drinking Water and Awareness of Its Health Risks in a Bangladeshi Population: Results from a Large Population-Based Study

Article

Full-text available

Apr 2006

We conducted a population-based prevalence survey in Araihazar, Bangladesh, to describe the distribution of arsenic exposure in a rural Bangladeshi population and to assess the population's awareness to this problem as well as to possible remediation options. Water samples from 5,967 contiguous tube wells in a defined geographic area were tested using laboratory-based methods. Additionally, for each well, the owner/caretaker (or a close relative) was interviewed regarding his or her awareness of the health consequences of As exposure. Arsenic exposure data and demographic characteristics for the 65,876 users of these wells were also collected from the 5,967 respondents. Among the 65,876 residents, more than half (54%) regularly consumed well water with an As concentration > or = 50 microg/L--above the acceptable government standard in Bangladesh. Respondents were 15-92 years of age, with an average age of 42 years, and 43% were male. Presence of awareness was significantly related to male sex, nonlabor head of household occupation, better housing, and having had the well tested for As concentration. Most respondents (92%) expressed a willingness to take steps to reduce their exposure, with switching to a safe well the most favored option (46.2%). Willingness to reduce exposure was positively related to awareness of the health risks of As. However, the association between awareness and switching to a safe well [odds ratio (OR) = 1.25; 95% confidence interval (CI), 1.01-1.54] was no stronger than the associations between awareness and using surface water (with or without treatments) (OR = 1.54; 95% CI, 1.22-1.95) or using an existing well after treatment or increasing the depth (OR = 1.34; 95% CI, 1.08-1.67). These findings suggest that health education programs may need to target individuals with lower socioeconomic status and that well switching should be encouraged with more appropriate health education. Increasing knowledge of the health consequences of As may be an important element in facilitating remediation.

Arsenic Exposure from Drinking Water and Risk of Premalignant Skin Lesions in Bangladesh: Baseline Results from the Health Effects of Arsenic Longitudinal Study

Article

Full-text available

Jul 2006
AM J EPIDEMIOL

Millions of persons around the world are exposed to low doses of arsenic through drinking water. However, estimates of health effects associated with low-dose arsenic exposure have been extrapolated from high-dose studies. In Bangladesh, many persons have been exposed to a wide range of doses of arsenic from drinking water over a significant period of time. The authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002 for the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for all arsenic exposure measures. Compared with drinking water containing <8.1 microg/liter of arsenic, drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 microg/liter of arsenic was associated with adjusted prevalence odds ratios of skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. These findings provide information that should be considered in future research and policy decisions.

Determination of Pb and Cd in whole blood using isotope dilution ICP-MS, in atomic spectroscopy

Article

Jan 1993

A. Stroh

Speciation analysis of arsenic in food samples with high performance liquid chromatography-inductively coupled plasma-mass spectrometry

Article

Nov 2003

The speciation of arsenic in food samples was analyzed. The methods used for sample preparation include: the extraction of arsenic from food samples using a 1:1 (v v) methanor water, and high performance liquid chroma tographyinductively coupled plasma-mass spectrometry (HPLC-ICP-MS) determination of the speciation of arsenic in food samples. A C18 column was used to separate the arsenic species. The mobile phase consists of 5 mmol L tetrabutylammonium hydride, 2 mmol L mabnic acid and 5 % (v v) methanol solution with the pH adjusted to 5.9. The mobile phase flow rate was 1.2 mL min. The chemical species of arsenic present in the foodstuffs were found mainly As (III), As (V), dimethylarsinic (V) (DMA (V)) Detection limit was based on signal to noise ratio of 3. As to apple samples, the detection limits were 0.2, 0.6 and 0.3 μg kg for As (III), As (V) and DMA (V), respectively. The concentrations of arsenic in raw apple samples were calculated.

Contamination of drinking water by arsenic in Bangladesh: A public health emergency

Article

Jan 2000
B WORLD HEALTH ORGAN

The contamination of groundwater by arsenic in Bangladesh is the largest poisoning of a population in history, with millions of people exposed. This paper describes the history of the discovery of arsenic in drinking-water in Bangladesh and recommends intervention strategies. Tube-wells were installed to provide "pure water" to prevent morbidity and mortality from gastrointestinal disease. The water from the millions of tube-wells that were installed was not tested for arsenic contamination. Studies in other countries where the population has had long-term exposure to arsenic in groundwater indicate that 1 in 10 people who drink water containing 500 mu g of arsenic per litre may ultimately die from cancers caused by arsenic, including lung, bladder and skin cancers. The rapid allocation of funding and prompt expansion of current interventions to address this contamination should be facilitated. The fundamental intervention is the identification and provision of arsenic-free drinking water. Arsenic is rapidly excreted in urine, and for early or mild cases, no specific treatment is required. Community education and participation are essential to ensure that interventions are successful; these should be coupled with follow-up monitoring to confirm that exposure has ended. Taken together with the discovery of arsenic in groundwater in other countries, the experience in Bangladesh shows that groundwater sources throughout the world that are used for drinking-water should be tested for arsenic.

Urinary creatinine concentrations in the U.S. population: implications for urinary biologic monitoring measurements

Article

Jan 2005

Development of Public Health Advisories for Arsenic in Drinking Water

Article

Jan 1999
Rev Environ Health

Paul B Tchounwou

Arsenic in the environment part II: Human health and ecosystem effects

Article

May 1995

W. Ternes

A Case-Cohort Design for Epidemiologic Cohort Studies and Disease Prevention Trials

Article

Apr 1986
BIOMETRIKA

R.L. Prentice

Suppose that a cohort of individuals is to be followed in order to relate failure rates to preceding covariate histories. A design is proposed which involves covariate data only for cases experiencing failure and for members of a randomly selected ubcohort. Odds ratio and relative risk estimation procedures are presented for such a 'case-cohort' design. A small simulation study compares ease-cohort relative risk estimation procedures to full-cohort and synthetic case-control analyses. Relevance to epidemiologic cohort studies and disease prevention trials is discussed.

Effects and Dose-Response Relationships of Skin Cancer and Blackfoot Disease with Arsenic

Article

Sep 1977

Wen-Ping Tseng

In a limited area on the southwest coast of Taiwan, where artesian well water with a high concentration of arsenic has been used for more than 60 years, a high prevalence of chronic arsenicism has been observed in recent years. The total population of this “endemic” area is approximately 100,000. A general survey of 40,421 inhabitants and follow-up of 1,108 patients with blackfoot disease were made. Blackfoot disease, so-termed locally, is a peripheral vascular disorder resulting in gangrene of the extremities, especially the feet. The overall prevalence rates for skin cancer was 10.6 per 1000, and for blackfoot disease 8.9 per 1000. Generally speaking, the prevalence increased steadily with age in both diseases. The prevalence rates for skin cancer and blackfoot disease increased with the arsenic content of well water, i.e., the higher the arsenic content, the more patients with skin cancer and blackfoot disease. A dose–response relationship between blackfoot disease and the duration of water intake was also noted. Furthermore, the degree of permanent impairment of function in the patient was directly related to duration of intake of arsenical water and to duration of such intake at the time of onset. The most common cause of death in the patients with skin cancer and blackfoot disease was carcinoma of various sites. The 5-year survival rate after the onset of blackfoot disease was 76.3%; the 10-year survival rate was 63.3% and 15-year survival rate, 52.2%. The 50% survival point was 16 years after onset of the disease. ImagesFIGURE 1.FIGURE 2.

Total arsenic in urine: Palladium-persulfate vs nickel as a matrix modifier for graphite furnace atomic absorption spectrophotometry

Article

Oct 1991

We evaluated the effectiveness of nickel and palladium with or without added potassium persulfate as matrix modifiers for the determination of total arsenic in urine. Complete recovery of pure aqueous solutions of As(III), As(V), cacodylic acid (DMA), monomethylarsinic acid (MMA), and o-arsanilic acid was attained by using both nickel and palladium modifiers. Combined arsenobetaine and arsenocholine (so-called fish arsenic), extracted from a certified control material of dogfish muscle (DORM-1), were completely recovered with Pd-S2O8 matrix modification, but not with nickel. Excellent agreement with target values for arsenic in urines from the Centre de Toxicologie du Quebec, supplied by the Interlaboratory Comparison Program, was attained irrespective of the arsenic source when we used Pd-S2O8 as the matrix modifier.

Arsenic and cancers [Letter]

Article

Mar 1988

Human retention studies with 74As. Toxicol Appl Pharmacol

Article

Jun 1980

An experiment is described in which the human metabolism of inorganic arsenic was investigated. Six volunteers took oral doses of 74As, and were measured in a whole body counter, for periods up to 103 days, with up to 39 separate measurements. Complete collections of their excreta were made for up to 7 days, and the 74As content was measured. The results indicate that the data are best represented by a three-component exponential function, the values of the coefficients for the pooled data being 65.9% with half-life of 2.09 days, 30.4% with a half-life of 9.5 days, and 3.7% with a half-life of 38.4 days.

Analysis of Case-Cohort Designs

Article

Jan 2000
J CLIN EPIDEMIOL

The case-cohort design is most useful in analyzing time to failure in a large cohort in which failure is rare. Covariate information is collected from all failures and a representative sample of censored observations. Sampling is done without respect to time or disease status, and, therefore, the design is more flexible than a nested case-control design. Despite the efficiency of the methods, case-cohort designs are not often used because of perceived analytic complexity. In this article, we illustrate computation of a simple variance estimator and discuss model fitting techniques in SAS. Three different weighting methods are considered. Model fitting is demonstrated in an occupational exposure study of nickel refinery workers. The design is compared to a nested case-control design with respect to analysis and efficiency in a small simulation. In this example, case-cohort sampling from the full cohort was more efficient than using a comparable nested case-control design.

Important considerations in the development of public health advisories for arsenic and arsenic-containing compounds in drinking water

Article

Oct 1999

Drinking water contamination by arsenic remains a major public health problem. Acute and chronic arsenic exposure via drinking water has been reported in many countries of the world; especially in Argentina, Bangladesh, India, Mexico, Thailand, and Taiwan, where a large proportion of drinking water (ground water) is contaminated with a high concentration of arsenic. Research has also pointed out significantly higher standardized mortality ratios and cumulative mortality rates for cancers of the bladder, kidney, skin, liver, and colon in many areas of arsenic pollution. General health effects that are associated with arsenic exposure include cardiovascular and peripheral vascular disease, developmental anomalies, neurologic and neurobehavioral disorders, diabetes, hearing loss, portal fibrosis of the liver, lung fibrosis, hematologic disorders (anemia, leukopenia, and eosinophilia), and carcinoma. Although, the clinical manifestations of arsenic poisoning appear similar, the toxicity of arsenic compounds depends largely u[on the chemical species and the form of arsenic involved. On the basis of its high degree of toxicity to humans, and the non-threshold dose-response assumption, a zero level exposure is recommended for arsenic, even though this level is practically non-attainable. In this review, we provide and discuss important information on the physical and chemical properties, production and use, fate and transport, toxicokinetics, systemic and carcinogenic health effects, regulatory and health guidelines, analytical methods, and treatment technologies that are applied to arsenic pollution. Such information is critical in assisting the federal, state and local officials who are responsible for protecting public health in dealing with the problem of drinking water contamination by arsenic and arsenic-containing compounds.

Associations Between Drinking Water and Urinary Arsenic Levels and Skin Lesions in Bangladesh

Article

Dec 2000

The present study examined the associations between drinking water and urinary arsenic levels and skin lesions among 167 residents of three contiguous villages in Bangladesh. Thirty-six (21.6%) had skin lesions (melanosis, hyperkeratosis, or both), of which 13 (36.1%) occurred in subjects who were currently drinking water containing concentrations of arsenic < 50 micrograms/L. The risk for skin lesions in relation to the exposure estimates based on urinary arsenic was elevated more than 3-fold, with the odds ratios for the highest versus the lowest quartiles being 3.6 (95% confidence interval, 1.2 to 12.1) for urinary total arsenic and 3.2 (95% confidence interval, 1.1 to 10.0) for urinary creatinine-adjusted total arsenic. The risks for skin lesions in relation to the exposure estimates based on arsenic in drinking water were less strongly elevated, with the odds ratios for the highest versus the lowest quartiles of exposure being 1.7 (95% confidence interval, 0.6 to 5.1) for drinking-water arsenic and 2.3 for cumulative arsenic index. The study suggests that arsenic exposure is associated with skin lesions in the Bangladesh population and that urinary arsenic may be a stronger predictor of skin lesions than arsenic in drinking water in this population.

Chronic Arsenic Toxicity in Bangladesh and West Bengal, India—A Review and Commentary

Article

Feb 2001
J Toxicol Clin Toxicol

Fifty districts of Bangladesh and 9 districts in West Bengal, India have arsenic levels in groundwater above the World Health Organization's maximum permissible limit of 50 microg/L. The area and population of 50 districts of Bangladesh and 9 districts in West Bengal are 118,849 km2 and 104.9 million and 38,865 km2 and 42.7 million, respectively. Our current data show arsenic levels above 50 microg/ L in 2000 villages, 178 police stations of 50 affected districts in Bangladesh and 2600 villages, 74 police stations/blocks of 9 affected districts in West Bengal. We have so far analyzed 34,000 and 101,934 hand tube-well water samples from Bangladesh and West Bengal respectively by FI-HG-AAS of which 56% and 52%, respectively, contained arsenic above 10 microg/L and 37% and 25% arsenic above 50 microg/L. In our preliminary study 18,000 persons in Bangladesh and 86,000 persons in West Bengal were clinically examined in arsenic-affected districts. Of them, 3695 (20.6% including 6.11% children) in Bangladesh and 8500 (9.8% including 1.7% children) in West Bengal had arsenical dermatological features. Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. The time of onset depends on the concentration of arsenic in the drinking water, volume of intake, and the health and nutritional status of individuals. Major dermatological signs are diffuse or spotted melanosis, leucomelanosis, and keratosis. Chronic arsenicosis is a multisystem disorder. Apart from generalized weakness, appetite and weight loss, and anemia, our patients had symptoms relating to involvement of the lungs, gastrointestinal system, liver, spleen, genitourinary system, hemopoietic system, eyes, nervous system, and cardiovascular system. We found evidence of arsenic neuropathy in 37.3% (154 of 413 cases) in one group and 86.8% (33 of 38 cases) in another. Most of these cases had mild and predominantly sensory neuropathy. Central nervous system involvement was evident with and without neuropathy. Electrodiagnostic studies proved helpful for the diagnosis of neurological involvement. Advanced neglected cases with many years of exposure presented with cancer of skin and of the lung, liver, kidney, and bladder. The diagnosis of subclinical arsenicosis was made in 83%, 93%, and 95% of hair, nail and urine samples, respectively, in Bangladesh; and 57%, 83%, and 89% of hair, nail, and urine samples, respectively in West Bengal. Approximately 90% of children below 11 years of age living in the affected areas show hair and nail arsenic above the normal level. Children appear to have a higher body burden than adults despite fewer dermatological manifestations. Limited trials of 4 arsenic chelators in the treatment of chronic arsenic toxicity in West Bengal over the last 2 decades do not provide any clinical, biochemical, or histopathological benefit except for the accompanying preliminary report of clinical benefit with dimercaptopropanesulfonate therapy. Extensive efforts are needed in both countries to combat the arsenic crisis including control of tube-wells, watershed management with effective use of the prodigious supplies of surface water, traditional water management, public awareness programs, and education concerning the apparent benefits of optimal nutrition.

Arsenic toxicity and potential mechanisms of action

Article

Aug 2002
TOXICOL LETT

Michael F Hughes

Exposure to the metalloid arsenic is a daily occurrence because of its environmental pervasiveness. Arsenic, which is found in several different chemical forms and oxidation states, causes acute and chronic adverse health effects, including cancer. The metabolism of arsenic has an important role in its toxicity. The metabolism involves reduction to a trivalent state and oxidative methylation to a pentavalent state. The trivalent arsenicals, including those methylated, have more potent toxic properties than the pentavalent arsenicals. The exact mechanism of the action of arsenic is not known, but several hypotheses have been proposed. At a biochemical level, inorganic arsenic in the pentavalent state may replace phosphate in several reactions. In the trivalent state, inorganic and organic (methylated) arsenic may react with critical thiols in proteins and inhibit their activity. Regarding cancer, potential mechanisms include genotoxicity, altered DNA methylation, oxidative stress, altered cell proliferation, co-carcinogenesis, and tumor promotion. A better understanding of the mechanism(s) of action of arsenic will make a more confident determination of the risks associated with exposure to this chemical.

Survey of arsenic in food composites from an arsenic-affected area of West Bengal, India

Article

Dec 2002
FOOD CHEM TOXICOL

An investigation of total arsenic in food composites, collected from the villagers, was carried out in arsenic-affected areas of the Murshidabad district, West Bengal where the agricultural system is mostly groundwater dependent. The shallow, large-diameter tubewells installed for agricultural irrigation contain an appreciable amount of arsenic (mean 0.085 mg/l, n=6). Even the soil is arsenic-contaminated (mean 11.35 mg/kg, n=36), so some arsenic can be expected in the food chain from crops cultivated in this area. The results revealed that the individual food composite and food groups containing the highest mean arsenic concentrations (microg/kg) are potato skin (292.62 and 104), leaf of vegetables (212.34 and 294.67), arum leaf (331 and 341), papaya (196.50 and 373), rice (226.18 and 245.39), wheat (7 and 362), cumin (47.86 and 209.75), turmeric powder (297.33 and 280.9), cereals and bakery goods (156.37 and 294.47), vegetables (91.73 and 123.22), spices (92.22 and 207.60) and miscellaneous items (138.37 and 137.80) for the Jalangi and Domkal blocks, respectively. Arsenic is absorbed by the skin of most of the vegetables. The arsenic concentration in fleshy vegetable material is low (mean 2.72 microg/kg, n=45). Higher levels of arsenic were observed in cooked items compared with raw. Daily dietary intakes of arsenic (microg) from the foodstuffs for adults are 171.20 and 189.13 and for children are 91.89 and 101.63 in the Jalangi and Domkal blocks, respectively.

An Overview on Peripheral Vascular Disease in Blackfoot Disease-Hyperendemic Villages in Taiwan

Article

Sep 2002

Chin-Hsiao Tseng

The arsenic-related peripheral vascular disease found to be endemic along the southwestern coast of Taiwan is reviewed. In the early 20th century a strange disease involving the lower extremities characterized by typical clinical symptoms and signs of progressive arterial occlusion was reported in a confined area located along the southwestern coast of Taiwan. The disease was locally called "blackfoot disease" because of its gangrenous appearance involving the feet of the patients. The prevalence of this disease ranged from 6.51 to 18.85 per 1,000 population in different villages. Epidemiologic studies revealed that blackfoot disease was associated with the consumption of artesian well water containing high levels of arsenic. High co-occurrence of blackfoot disease and arsenic-related skin lesions such as hyperpigmentation, hyperkeratosis, and skin cancer was also observed. Recent studies also confirmed the association of preclinical peripheral vascular disease with arsenic exposure in a dose-response pattern. Subclinical arterial insufficiency and defects in cutaneous microcirculation can also be demonstrated in seemingly normal subjects living in the endemic villages. The incidence of clinical manifestation of blackfoot disease decreased dramatically after the implementation of tap water in these villages over the past 2-3 decades. The atherogenicity of arsenic could be associated with its effects on hypercoagulability, endothelial injury, smooth muscle cell proliferation, somatic mutation, oxidative stress, and apoptosis. However, its interaction with some trace elements and its association with hypertension and diabetes mellitus could also explain part of its higher risk of developing atherosclerosis.

Article

Oct 2002

To assess the health effects of arsenic poisoning and to determine the relationship among duration and severity of skin lesions, exposure dose of arsenic, and nutritional status of people, 150 patients attending the Dermatology Outpatients Department of Sher-e-Bangla Medical College Hospital, Barisal, Bangladesh, were included in this cross-sectional study. The study was conducted during January-December 2000. Records of patients were collected prospectively using a pre-tested questionnaire, which included information on demography, sources of water for drinking and cooking, duration and amount of drinking-water obtained from shallow tubewells, clinical presentations, complications, and physical and laboratory findings. Water samples from tubewells currently being used by individual patients were examined. Nine percent of the patients were unaware that arsenic-contaminated water causes diseases. Due to lack of alternative water supplies, 25% of the subjects were still drinking water from contaminated tubewells. About 18% did not complain of any clinical symptoms, except that their skin lesions were ugly-looking, and 82% had moderate or severe skin lesions. Thirty-one percent of the water samples had arsenic concentrations 10-fold higher than the permissible limit of 0.05 mg/L in Bangladesh and 50-fold higher than the WHO guideline value of 0.01 mg/L. The mean arsenic concentration in water was significantly associated with the severity of disease. Body mass index correlated inversely (r = -0.298, p = 0.013) with the duration of disease after controlling for age. The findings suggest the need to enhance public awareness on negative health effects of arsenic poisoning in rural Bangladesh. From a public-health perspective, effective intervention strategies need to be developed to curb the exposure, strengthen rapid diagnostic facilities, establish effective treatment facilities in rural areas, and improve the nutritional status of people.

Skin manifestations of arsenicosis in two villages in Bangladesh

Article

Jan 2003
INT J DERMATOL

Arsenic contamination in groundwater affects 35 million people in Bangladesh, but the prevalence of arsenic contamination in local communities remains to be clarified. As skin manifestations are sensitive markers of arsenicosis, we examined the skin of adults and adolescents in two villages to elucidate the severity of arsenicosis. Five hundred and sixty-one villagers were randomly selected for the evaluation of their skin. Three indicators, i.e. keratosis on the soles, keratosis on the palms, and melanosis and hypopigmentation on the trunk, were quantified for analysis. More than 50% of the villagers showed some skin manifestations due to arsenicosis. Keratosis on the soles was the most sensitive marker for the detection of arsenicosis at an early stage. Interestingly, the skin manifestations were more severe in males than in females. There was no correlation between the age and the severity of skin manifestations. The prevalence of arsenicosis was quite high and males were more vulnerable to arsenic contamination. Using skin manifestations, especially keratosis on the soles, as useful markers to detect and evaluate arsenicosis, it is clear that there is an urgent need to assess the exact prevalence and severity of arsenicosis in the population of Bangladesh in order to take measures to treat and control this problem.

Arsenic in Drinking Water and Skin Lesions: Dose-Response Data from West Bengal, India

Article

Apr 2003
EPIDEMIOLOGY

Over 6 million people live in areas of West Bengal, India, where groundwater sources are contaminated with naturally occurring arsenic. The key objective of this nested case-control study was to characterize the dose-response relation between low arsenic concentrations in drinking water and arsenic-induced skin keratoses and hyperpigmentation. We selected cases (persons with arsenic-induced skin lesions) and age- and sex-matched controls from participants in a 1995-1996 cross-sectional survey in West Bengal. We used a detailed assessment of arsenic exposure that covered at least 20 years. Participants were reexamined between 1998 and 2000. Consensus agreement by four physicians reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases clinically diagnosed in the field. The average peak arsenic concentration in drinking water was 325 microg/liter for cases and 180 microg/liter for controls. The average latency for skin lesions was 23 years from first exposure. We found strong dose-response gradients with both peak and average arsenic water concentrations. The lowest peak arsenic ingested by a confirmed case was 115 microg/liter. Confirmation of case diagnosis and intensive longitudinal exposure assessment provide the basis for a detailed dose-response evaluation of arsenic-caused skin lesions.

Searching for an optimum solution to the Bangladesh arsenic crisis

Article

Jun 2003

Searching for an optimum solution to the Bangladesh arsenic crisis: Thirty years ago Bangladesh experienced very high levels of infant and child mortality, much of it due to water-borne disease in deltaic conditions where surface water was highly polluted. In what appeared to be one of the great public health achievements, 95% of the population were converted to drinking bacteria-free tubewell water from underground aquifers. Recently, it has been shown that perhaps 20% of this water is arsenic contaminated and alternatives to tubewell water have been sought. This paper reports on two national surveys collaboratively carried out in 2000 by the Health Transition Centre, Australian National University and Mitra and Associates, Dhaka: A census of tubewells and a household survey of tubewell use and arseniosis. The study found that the tubewell revolution has been promoted not only by health considerations but also by the demand for a household water facility and the desire by women to reduce workloads associated with using surface water. Because of this, and because the population had absorbed the message about safe tubewell water, it is argued that the movement away from the use of tubewell water should be as limited as possible, even if this means using safe tubewells which are often found in the neighbourhood. To enable such a move the most urgent need is not changing the source of water but comprehensive national water testing providing essential information to households about which wells are safe and which are not.

Element speciation definitions, analytical methodology, and some examples

Article

Oct 2003

Bernhard Michalke

This paper gives definitions related to element speciation and the reasons for the need for speciation. The problems focused on, involve sampling, sample preparation and storage, as well as changes in species information that occur during the use of various separation technologies. However, the potential and advantages of the separation methods in element speciation are also discussed. In addition, problems arising during element detection that are attributable to analytes or mobile-phase composition are outlined, as well as the pronounced advantages of detection by inductively coupled plasma-mass spectrometry (ICP-MS). The combination of the various separation systems with element- or molecule-specific detectors creates problems especially in element speciation. These difficulties are described along with recent developments for overcoming them or for improving their coupling efficiency. Finally, several elements for which the issue of speciation is important are discussed, with examples from some recent publications on arsenic, selenium and iodine speciation.

Arsenic toxicity at low doses: Epidemiological and mode of action considerations

Article

Sep 2004

Current approaches to risk assessment typically assume a linear dose-response for mutagenic compounds that directly interact with DNA or when the carcinogenic mechanism is unknown. Because the mode of action of arsenic-induced carcinogenesis is not well established, recent dose-response assessments for arsenic have assumed linearity at low doses despite evidence that arsenic is not a direct-acting mutagen. Several modes of action, including generation of oxidative stress, perturbation of DNA methylation patterns, inhibition of DNA repair, and modulation of signal transduction pathways, have been proposed to characterize arsenic's toxicity. It is probable that these mechanisms do not act in isolation, but overlap, and contribute to the complex nature of arsenic-induced carcinogenesis. All of the proposed mechanisms are likely to be nonlinear at low does. Furthermore, studies of populations outside the US exposed to arsenic in drinking water show increases in cancer only at relatively high concentrations, that is, concentrations in drinking water of several hundred micrograms per liter (microg/l). Studies in the US of populations exposed to average concentrations in drinking water up to about 190 microg/l do not provide evidence of increased cancer. Consideration of arsenic's plausible mechanisms and evidence from epidemiological studies support the use of nonlinear methods, either via biologically based modeling or use of a margin-of-exposure analysis, to characterize arsenic risks.

Arsenic Crisis in Bangladesh

Article

Sep 2004

Ahmed Mushtaque R Chowdhury

The problem of arsenic poisoning by drinking water in Bangladesh is discussed. Many people in the country are suffering from skin lesions due to arsenic poisoning from tubewell water. In response to the crisis, the government created the Bangladesh Arsenic Mitigation and Water Supply Project in 1998, to which effort the World Bank provided a loan of $32.5 million. The Bangladesh Rural Advancement Committee (BRAC), a nongovernmental organization have also been working to find a solution to the arsenic problem. The pond sand filter and three-pitcher filter are some technologies that are examined for providing pathogen free surface water for human consumption.

Arsenic and its speciation analysis using high-performance liquid chromatography and inductively coupled plasma mass spectrometry

Article

Sep 2004
J CHROMATOGR A

It is known that arsenic has different toxicological properties dependent upon both its oxidation state for inorganic compounds, as well as the different toxicity levels exhibited for organic arsenic compounds. The field of arsenic speciation analysis has grown rapidly in recent years, especially with the utilization of high-performance liquid chromatography (HPLC) coupled to inductively coupled plasma mass spectrometry (ICP-MS), a highly sensitive and robust detector system. Complete characterization of arsenic compounds is necessary to understand intake, accumulation, transport, storage, detoxification and activation of this element in the natural environment and living systems. This review describes the essential background and toxicity of arsenic in the environment, and more importantly, some currently used chromatographic applications and sample handling procedures necessary to accurately detect and quantify arsenic in its various chemical forms. Applications and work using only HPLC-ICP-MS for arsenic speciation of environmental and biological samples are presented in this review.

Limited Temporal Variability of Arsenic Concentrations in 20 Wells Monitored for 3 Years in Araihazar, Bangladesh

Article

Aug 2005

Millions of people in Bangladesh have probably switched their water consumption to wells that meet the local standard for As in drinking water of 50 microg/L as a result of blanket field testing throughout the country. It is therefore important to know if As concentrations in those wells could change over time. To address this issue, we report here precise groundwater As analyses for time-series samples collected from a suite of 20 tube wells containing < or =50 microg/L As and ranging from 8 to 142 m in depth. For 17 out of 20 wells, the standard deviation of groundwater As concentrations was <10 microg/L over the 3-year monitoring period (n = 24-44 per well). Six of the 17 wells are community wells, each of which serves the needs of several hundred people in particularly affected villages. Of the three wells showing larger fluctuations in chemical composition including As, two are very shallow (8 and 10 m). Variations in As concentrations for one of these wells (50 +/- 32 microg/L, n = 36), as well as another shallow well showing smaller variations (48 +/- 5 microg/L, n = 36), appear to be coupled to seasonal precipitation and recharge linked to the monsoon. The other shallow well showing larger variations in composition indicates a worrisome and steady increase in As concentrations from 50 to 70 microg/L (n = 36) over 3 years. The time series of As (30 +/- 11 microg/L, n = 24) and other constituents in one deep community well (59 m) show large fluctuations that suggest entrainment of shallow groundwater through a broken PVC pipe. Even though the majority of wells that were initially safe remained so for 3 years, our results indicate that tube wells should be tested periodically.

Arsenic toxicity, mutagenesis, and carcinogenesis - A health risk assessment and management approach

Article

Feb 2004

A comprehensive analysis of published data indicates that arsenic exposure induces cardiovascular diseases, developmental abnormalities, neurologic and neurobehavioral disorders, diabetes, hearing loss, hematologic disorders, and various types of cancer. Although exposure may occur via the dermal, and parenteral routes, the main pathways of exposure include ingestion, and inhalation. The severity of adverse health effects is related to the chemical form of arsenic, and is also time- and dose-dependent. Recent reports have pointed out that arsenic poisoning appears to be one of the major public health problems of pandemic nature. Acute and chronic exposure to arsenic has been reported in several countries of the world where a large proportion of drinking water (groundwater) is contaminated with high concentrations of arsenic. Research has also pointed significantly higher standardized mortality rates for cancers of the bladder, kidney, skin, liver, and colon in many areas of arsenic pollution. There is therefore a great need for developing a comprehensive health risk assessment (RA) concept that should be used by public health officials and environmental managers for an effective management of the health effects associated with arsenic exposure. With a special emphasis on arsenic toxicity, mutagenesis, and carcinogenesis, this paper is aimed at using the National Academy of Science's RA framework as a guide, for developing a RA paradigm for arsenic based on a comprehensive analysis of the currently available scientific information on its physical and chemical properties, production and use, fate and transport, toxicokinetics, systemic and carcinogenic health effects, regulatory and health guidelines, analytical guidelines and treatment technologies.

Modification of Risk of Arsenic-Induced Skin Lesions by Sunlight Exposure, Smoking, and Occupational Exposures in Bangladesh

Article

Jul 2006
EPIDEMIOLOGY

The risk of skin lesions associated with arsenic exposure from drinking water in Bangladesh is considerably greater in men than in women. Using baseline data from 11,062 cohort members in the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh, we performed a cross-sectional analysis to evaluate whether the association between arsenic exposure from drinking water and the risk of skin lesions is modified by tobacco smoking, excessive sunlight, the use of fertilizer, and the use of pesticides. A time-weighted well arsenic concentration was estimated for each participant by incorporating history of well use. Relative excess risk for interaction (RERI) and its 95% confidence intervals (CIs) were estimated using adjusted prevalence odds ratios. We observed a synergistic effect between the highest level of arsenic exposure (> 113 microg/L) and tobacco smoking on risk of skin lesions in men (RERI = 1.5 [95% CI = 0.3 to 2.7] overall and 1.7 [0.2 to 3.4] for the subpopulation with longer-term arsenic exposure). We also observed suggestive synergistic effects between higher levels (28.1-113.0 microg/L and 113.1-864.0 microg/L) of arsenic exposure and fertilizer use in men (RERI = 1.0 [-0.2 to 2.2] and 1.3 [-0.2 to 2.9] respectively). Furthermore, the risk of skin lesions associated with any given level of arsenic exposure was greater in men with excessive sun exposure. The patterns of effect estimates in women indicate similar-but-weaker interaction effects of arsenic exposure with tobacco smoking and fertilizer use. These findings help explain why the risk of arsenic-related skin lesions was much greater in men than in women in Bangladesh. Because most arsenic-induced skin cancers arise from these skin lesions, treatment and remediation plans should take into consideration these etiologic cofactors.

Dose–response relationship between arsenic exposure from drinking water and risk of skin lesions in Bangladesh population: baseline results from Health Effects of r232 M

225-233

H Ahsan
Y Chen
F Parvez
L Zablotska
I Hussain
H Momo-Tai
D Levy
Z Cheng
V Slavkovich
A Geen
G R Howe
J H Graziano

Ahsan, H., Chen, Y., Parvez, F., Zablotska, L., Hussain, I., Momo-tai, H., Levy, D., Cheng, Z., Slavkovich, V., van Geen, A., Howe, G.R., Graziano, J.H., 2006b. Dose–response relationship between arsenic exposure from drinking water and risk of skin lesions in Bangladesh population: baseline results from Health Effects of r232 M. Hall et al. / Toxicology 225 (2006) 225–233 Arsenic Longitudinal Study (HEALS). Am. J. Epidemiol. 163, 1138–1148

Arsenic crisis in Bangladesh Urinary creatinine and arsenic metabolism A442 (author reply A442–A443) Gamble Folate, homocysteine, and arsenic metabolism in arsenic-exposedindividualsinBangladesh Arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain area

86-91

A M Chowdhury
M V Gamble
X Liu
M V Liu
X Ahsan
H Pilsner
R Ilievski
V Slavkovich
V Parvez
F Levy
D Factor
P Litvak
J H Graziano

Chowdhury, A.M., 2004. Arsenic crisis in Bangladesh. Sci. Am. 291, 86–91. Gamble, M.V., Liu, X., 2005. Urinary creatinine and arsenic metabolism. Environ. Health Perspect. 113, A442 (author reply A442–A443). Gamble, M.V., Liu, X., Ahsan, H., Pilsner, R., Ilievski, V., Slavkovich, V., Parvez, F., Levy, D., Factor-Litvak, P., Graziano, J.H., 2005. Folate, homocysteine, and arsenic metabolism in arsenic-exposedindividualsinBangladesh.Environ.HealthPerspect.113, 1683–1688. Guo, X., Fujino, Y., Kaneko, S., Wu, K., Xia, Y., Yoshimura, T., 2001. Arsenic contamination of groundwater and prevalence of arsenical dermatosis in the Hetao plain area, Inner Mongolia, China. Mol

Blood arsenic as a biomarker of arsenic exposure: Results from a prospective study

Abstract

No full-text available

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