Arsenic exposure in northern Mexican women.

OBJECTIVE: To describe interindividual metabolism variations and sociodemographic characteristics associated to urinary arsenic, and to estimate the arsenic contamination in water from urinary total arsenic (TAs). MATERIALS AND METHODS: Women (n=1 028) from northern Mexico were interviewed about their sociodemographic characteristics and their urinary concentrations of arsenic species were measured by liquid chromatography. Inorganic arsenic (iAs) in water was estimated from urinary TAs. RESULTS: Women were 20-88 years old. TAs in urine ranged from p10=3.41 to p90=56.93 µg/L; 74% of women had levels >6.4 µg/L. iAs in water varied from p10=3.04 to p90=202.12 µg/L; 65% of women had concentrations >10 µg/L, and 41%, concentrations >25 µg/L. Large variations in iAs metabolism were observed. TAs was significantly negatively associated with age and schooling, and positively with the state of residence. CONCLUSIONS: Exposure to iAs is an environmental problem in Mexico. Individual variations in metabolism are a challenge to design prevention and control programs.

OBJETIVO: Describir las variaciones interindividuales del metabolismo y las características sociodemográficas asociadas con el arsénico urinario, así como estimar su contaminación en el agua. MATERIAL Y MÉTODOS: Se entrevistó a 1 028 mujeres del norte de México; por cromatografía de líquidos se midieron los metabolitos urinarios de arsénico y, a partir de ellos, se estimó la concentración en agua. RESULTADOS: Las mujeres tuvieron 20-88 años. El arsénico urinario varió de p10=3.41 a p90=56.93 µg/L; 74% de las mujeres tuvieron niveles >6.4 µg/L. El arsénico en agua varió de p10=3.04 a p90=202.12 µg/L; 65% de las mujeres tenían concentraciones >10 µg/L, y 41%, >25 µg/L. Se observaron amplias variaciones en el metabolismo del arsénico. El arsénico urinario se asoció negativamente con la edad y escolaridad, y positivamente con el estado de residencia. CONCLUSIONES: La exposición a arsénico es un problema ambiental en México. Las variaciones individuales en su metabolismo son un desafío para diseñar programas de prevención y control.

Arsenic exposure in northern Mexican women / Exposición a arsénico en mujeres del norte de México

Abstract: Objective: To describe interindividual metabolism variations and sociodemographic characteristics associated to urinary arsenic, and to estimate the arsenic contamination in water from urinary total arsenic (TAs). Materials and methods: Women (n=1 028) from northern Mexico were interviewed about their sociodemographic characteristics and their urinary concentrations of arsenic species were measured by liquid chromatography. Inorganic arsenic (iAs) in water was estimated from urinary TAs. Results: Women were 20-88 years old. TAs in urine ranged from p10=3.41 to p90=56.93 μg/L; 74% of women had levels >6.4 μg/L. iAs in water varied from p10=3.04 to p90=202.12 μg/L; 65% of women had concentrations >10 μg/L, and 41%, concentrations >25 μg/L. Large variations in iAs metabolism were observed. TAs was significantly negatively associated with age and schooling, and positively with the state of residence. Conclusion: Exposure to iAs is an environmental problem in Mexico. Individual variations in metabolism are a challenge to design prevention and control programs.

Resumen: Objetivo: Describir las variaciones interindividuales del metabolismo y las características sociodemográficas asociadas con el arsénico urinario, así como estimar su contaminación en el agua. Material y métodos. Se entrevistó a 1 028 mujeres del norte de México; por cromatografía de líquidos se midieron los metabolitos urinarios de arsénico y, a partir de ellos, se estimó la concentración en agua. Resultados: Las mujeres tuvieron 20-88 años. El arsénico urinario varió de p10=3.41 a p90=56.93 μg/L; 74% de las mujeres tuvieron niveles >6.4 μg/L. El arsénico en agua varió de p10=3.04 a p90=202.12 μg/L; 65% de las mujeres tenían concentraciones >10 μg/L, y 41%, >25 μg/L. Se observaron amplias variaciones en el metabolismo del arsénico. El arsénico urinario se asoció negativamente con la edad y escolaridad, y positivamente con el estado de residencia. Conclusión: La exposición a arsénico es un problema ambiental en México. Las variaciones individuales en su metabolismo son un desafío para diseñar programas de prevención y control.

Speciation analysis of arsenic in samples containing high concentrations of chloride by LC-HG-AFS.

Chloride widely exists in the environment and will cause serious interference for arsenic speciation analysis. The determination of four arsenic species including arsenite (As(III)), arsenate (As(V)), monomethylarsenate (MMA), and dimethylarsonate (DMA) in samples containing high concentrations of Cl- was carried out in this work by coupling of liquid chromatography (LC) with hydride generation atomic fluorescence spectrometry (HG-AFS). The interference of Cl- was successfully eliminated by coupling two anion-exchange chromatographic columns in series and eluting with 35.0 mmol L-1 (NH4)2HPO4 (pH = 6.00). A novel pre-treatment system was subsequently developed to realize on-line column switch and pre-reduction of As(V). The analysis time was shortened by an isocratic elution but programmed flow rate method, and the sensitivity of As(V) was also enhanced by the introduction of pre-reduction using the developed system. The proposed method can resist at least 10 g L-1 Cl- without any pre-treatment operations. Since LC-HG-AFS is low-cost and can be afforded or self-assembled by most labs, the developed method can be adopted as a routine analysis method for arsenic species in chloride-bearing samples, such as urine and seawater. Graphical abstract.

Association of plasma folate, vitamin B12 levels, and arsenic methylation capacity with developmental delay in preschool children in Taiwan.

Developmental delay has been associated with inefficient arsenic methylation capacity in preschool children. Folate and vitamin B12 are important nutrients that produce s-adenosylmethionine during single-carbon metabolism and provide methyl groups for arsenic methylation. The aim of the present study was to explore whether plasma folate and vitamin B12 levels influence arsenic methylation capacity and in turn are related to developmental delay in preschool children. A case-control study was conducted in 178 children with developmental delay and 88 normal children, who were recruited from Shin Kong Wu Ho-Su Memorial Teaching Hospital from August 2010 to March 2014. Arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) in the urine was determined by high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Plasma folate and vitamin B12 levels were measured using a SimulTRAC-SNB radioassay. The results show that the combination of high plasma folate and high vitamin B12 levels were correlated with efficient arsenic methylation capacity (low MMAV %, low InAs %, and high DMAV %). High MMAV % significantly increased and high DMAV % and secondary methylation index decreased the odds ratio (OR) of developmental delay in a dose-dependent manner in both low plasma folate and low vitamin B12 (low/low) groups; the multivariate OR and 95% confidence interval were 5.01 (0.83-30.06), 0.21 (0.04-1.23), and 0.20 (0.03-1.20), respectively. This is the first study to show that the combination of high plasma folate and high vitamin B12 levels increases arsenic methylation capacity and indirectly decreases the OR of developmental delay in preschool children.

A semiparametric imputation approach for regression with censored covariate with application to an AMD progression study.

This research is motivated by studying the progression of age-related macular degeneration where both a covariate and the response variable are subject to censoring. We develop a general framework to handle regression with censored covariate where the response can be different types and the censoring can be random or subject to (constant) detection limits. Multiple imputation is a popular technique to handle missing data that requires compatibility between the imputation model and the substantive model to obtain valid estimates. With censored covariate, we propose a novel multiple imputation-based approach, namely, the semiparametric two-step importance sampling imputation (STISI) method, to impute the censored covariate. Specifically, STISI imputes the missing covariate from a semiparametric accelerated failure time model conditional on fully observed covariates (Step 1) with the acceptance probability derived from the substantive model (Step 2). The 2-step procedure automatically ensures compatibility and takes full advantage of the relaxed semiparametric assumption in the imputation. Extensive simulations demonstrate that the STISI method yields valid estimates in all scenarios and outperforms some existing methods that are commonly used in practice. We apply STISI on data from the Age-related Eye Disease Study, to investigate the association between the progression time of the less severe eye and that of the more severe eye. We also illustrate the method by analyzing the urine arsenic data for patients from National Health and Nutrition Examination Survey (2003-2004) where the response is binary and 1 covariate is subject to detection limit.

Using urine as a biomarker in human exposure risk associated with arsenic and other heavy metals contaminating drinking groundwater in intensively agricultural areas of Thailand.

Urine used as a biomarker was collected and compared between two groups of participants: (1) a groundwater-drinking group and (2) a non-groundwater-drinking group in intensively agricultural areas in Ubon Ratchathani province, Thailand. The statistical relationship with the metal concentration in shallow groundwater wells was established with urine data. According to the groundwater data, the health risk assessment results for four metals appeared to be higher for participants who drank groundwater than for the other group. The carcinogenic risk and non-carcinogenic risk of arsenic (As) were found in 25.86 and 31.03% of participants, respectively. For lead (Pb), 13.79% of the participants had a non-carcinogenic risk. Moreover, 30 of the 58 participants in the groundwater-drinking group had As urine higher than the standard, and 26, 2 and 9 of the 58 participants had above-standard levels for cadmium (Cd), Pb and mercury (Hg) in urine, respectively. Both the risk assessment and biomarker level of groundwater-drinking participants were higher than in the other group. The results showed an average drinking rate of approximately 4.21 ± 2.73 L/day, which is twice as high as the standard. Interestingly, the As levels in the groundwater correlated with those in the urine of the groundwater-drinking participants, but not in the non-groundwater-drinking participants, as well as with the As-related cancer and non-carcinogenic risks. The hazard index (HI) of the 100 participants ranged from 0.00 to 25.86, with an average of 1.51 ± 3.63 higher than the acceptable level, revealing that 28 people appeared to have non-carcinogenic risk levels (24 and 4 people for groundwater-drinking participants and non-groundwater-drinking participants, respectively). Finally, the associated factors of heavy metals in urine were the drinking water source, body weight, smoking, sex and use of personal protective equipment.

Distinct arsenic metabolites following seaweed consumption in humans.

Seaweeds contain arsenic primarily in the form of arsenosugars, which can be metabolized to a wide range of arsenic compounds. To characterize human exposure to arsenic from seaweed consumption, we determined concentrations of arsenic species in locally available seaweeds, and assessed urinary arsenic compounds in an experimental feeding study. A total of 11 volunteers consumed 10 g per day of three types of seaweeds (nori, kombu, and wakame) for three days each, while abstaining from rice and seafood following a three-day washout period. Urinary arsenosugars and their metabolites (including dimethyl arsenate (DMA), thio-dimethylarsinoylethanol (thio-DMAE), thio-dimethylarsinoylacetate (thio-DMAA), and thio-DMA) were measured in spot urine samples prior to seaweed consumption, and in 24-hour urine samples while consuming seaweed. Commercial products made from whole seaweed had substantial concentrations of arsenic (12-84 µg/g), dominated by arsenosugars. Intact arsenosugars along with DMA, thio-DMAA, thio-DMAE all increased in urine after ingesting each type of seaweed, and varied between seaweed types and between individuals. Only trace levels of the known toxic metabolite, thio-DMA, were observed, across individuals. Thio-DMAE and thio-DMAA are unique products of arsenosugar breakdown, thus assessment of these compounds may help to identify dietary intake of arsenic from seaweed from other exposure pathways.

Effects of phosphate binders on the gastrointestinal absorption of arsenate and of an SGLT2 inhibitor drug on the urinary excretion of arsenite in mice.

Arsenate (AsV) and arsenite (AsIII) are typical sources of acute and chronic arsenic poisoning. Therefore, reducing inner exposure to these arsenicals is a rational objective. Because AsV mimics phosphate, phosphate binder drugs may decrease the intestinal AsV absorption. Indeed, lanthanum and aluminium salts and sevelamer removed AsV from solution in vitro, especially at acidic pH. In mice gavaged with AsV, lanthanum chloride, lanthanum carbonate and aluminium hydroxide given orally also lowered the urinary excretion and tissue levels of AsV and its metabolites, indicating that they decreased the gastrointestinal AsV absorption. As some glucose transporters may carry AsIII, the effect of the SGLT2 inhibitor dapagliflozin was investigated in AsIII-injected mice. While producing extreme glucosuria, dapagliflozin barely affected the urinary excretion and tissue concentrations of AsIII and its metabolites. Thus, phosphate binders (especially lanthanum compounds) can reduce the gastrointestinal absorption of AsV; however, SGLT2 inhibition cannot diminish the renal reabsorption of AsIII.

Biomonitoring of arsenic in woodworkers exposed to CCA and evaluation of other non-occupational sources in Uruguay.

In Uruguay wood-impregnation plants use chromated copper arsenate (CCA) as preservative applying good manufacture practices (GMP). This study aims a retrospective evaluation of toxicologically relevant species levels in CCA exposed woodworker's urine (As-U) and an assessment of the effects of work risk factors and non-occupational sources in As-U of workers from a selected plant. From 2014 to 2016, As-U in 212 urine samples (As-U) of 73 woodworkers from six CCA impregnation plants were determined. In one of these plants, 35 workers were interviewed to obtain individual data of work tasks, lifestyles, diet, habits, etc. that may contribute to their overall exposure to Arsenic. Responses were statistically evaluated. Out of the 212 urine samples from 73 woodworkers, 96% showed lower levels of As-U than those established by health regulations (<35µgL-1). According to their work tasks 34% of 35 surveyed workers showed high exposure risk to As and 29% moderate exposure risk. Although they have lower levels of As-U owing to their personal protective equipment, As-U significantly correlate to work risk factors. Consumption of bottled water could also contribute to As-U levels as a non-occupational source. These results confirm that efforts of Uruguayan authorities to promote GMP were successful and justify the importance and frequency of As-U systematic biomonitoring for occupational risk assessment. A significant accomplishment of this work is that non-occupational sources of As-like bottled water consumption should also be considered in future studies.

Metabolism and toxicity of arsenicals in mammals.

Arsenic (As) is a metalloid usually found in organic and inorganic forms with different oxidation states, while inorganic form (arsenite As-III and arsenate As-v) is considered to be more hazardous as compared to organic form (methylarsonate and dimethylarsinate), with mild or no toxicity in mammals. Due to an increasing trend to using arsenicals as growth promoters or for treatment purposes, the understanding of metabolism and toxicity of As gets vital importance. Its toxicity is mainly depends on oxi-reduction states (As-III or As-v) and the level of methylation during the metabolism process. Currently, the exact metabolic pathways of As have yet to be confirmed in humans and food producing animals. Oxidative methylation and glutathione conjugation is believed to be major pathways of As metabolism. Oxidative methylation is based on conversion of Arsenite in to mono-methylarsonic acid and di-methylarsenic acid in mammals. It has been confirmed that As is only methylated in the presence of glutathione or thiol compounds, suggesting that As is being methylated in trivalent states. Subsequently, non-conjugated trivalent arsenicals are highly reactive with thiol which converts the trivalent arsenicals in to less toxic pentavalent forms. The glutathione conjugate stability of As is the most important factor for determining the toxicity. It can lead to DNA damage by alerting enzyme profile and production of reactive oxygen and nitrogen species which causes the oxidative stress. Moreover, As causes immune-dysfunction by hindering cellular and humeral immune response. The present review discussed different metabolic pathways and toxic outcomes of arsenicals in mammals which will be helpful in health risk assessment and its impact on biological world.

Diallyl trisulfide ameliorates arsenic-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

The present study investigates the possible ameliorative effects of diallyl trisulfide (DATS) against arsenic (As)-induced hepatotoxicity and oxidative stress in rats. The four experimental groups evaluated include: (1) vehicle control; (2) As (5 mg/kg/day); (3) DATS (80 mg/kg/day) + As; and (4) DATS. Induction of As in rats caused severe hepatotoxicity as evidenced by an elevation of serum aspartate aminotransferase and alanine aminotransferase activities and increased total bilirubin concentration, indicating hepatic function abnormalities. Histopathological examination revealed various structural changes in the liver, characterized by hepatocyte degeneration/necrosis, congestion, sinusoidal dilatation, vacuolation, and inflammatory cell infiltration. The significant decrease in reduced glutathione content, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and the significant increase in lipid peroxidation (thiobarbituric acid reactive substance) and protein oxidation (protein carbonyl) contents indicated that As-induced hepatotoxicity was mediated through oxidative stress. As intoxication also elevated the levels of Cas-3 and nitric oxide and increased the expression of nuclear factor-κB p65 in the liver. In contrast, DATS pretreatment significantly improved As-induced serum biochemical, immunohistochemical, and histopathological alterations reflecting hepatic dysfunction. These results may contribute to a better understanding of the hepatoprotective role of DATS, emphasizing the influence of this garlic trisulfide in the diet for human health, possibly preventing the hepatic injury associated with As intoxication, presumably due to its ability to inhibit lipid peroxidation, protein oxidation, and restoration of antioxidant status.

Arsenic methylation capacity and obesity are associated with insulin resistance in obese children and adolescents.

The goal of the present study was to compare the arsenic methylation capacities in elementary school and junior high school students in an area of Taiwan with low arsenic exposure, and explore the influence of both arsenic methylation capacity and obesity on insulin resistance in these children and adolescents using the HOMA-IR index. We recruited 303 elementary school students and 319 junior high school students in Taipei City from September 2007 to November 2011. Concentrations of inorganic arsenic (arsenite + arsenate), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) were determined by a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Insulin resistance was determined by HOMA-IR. Elementary school students had significantly lower inorganic arsenic percentage and a higher DMA(V) percentage than junior high school students. It seems that the former had better arsenic methylation capability than the latter. The HOMA-IR value was significantly and positively related to the sum of the urinary inorganic and methylated arsenic (TotalAs) concentrations and also the BMI Z score, with the regression coefficients (ß) being 0.058 (p < 0.001) and 0.001 (p = 0.027), respectively. The higher BMI values and higher TotalAs concentration were associated with higher HOMA-IR values in children and adolescents in Taiwan.

Arsenic methylation capacity and developmental delay in preschool children in Taiwan.

Environmental exposure to lead or mercury can cause neurodevelopmental damage. Arsenic is another neurotoxicant that can affect intellectual function in children. This study was designed to explore the difference of arsenic methylation capacity indices between with and without developmental delay in preschool children. We also aimed to identify whether blood levels of lead or mercury modify the effect of arsenic methylation capacity indices. A cross sectional study was conducted from August 2010 to March 2012. All participants recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In all, 63 children with developmental delay and 35 children without developmental delay were recruited. Urinary arsenic species, including arsenite (As(III)), arsenate (As(V)), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) were measured with a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Lead and mercury levels of red blood cells were measured by inductively coupled mass spectrometry. All participants underwent developmental assessments to confirm developmental delays, including evaluations of gross motor, fine motor, speech-language, cognition, social, and emotional domains. Urinary total arsenic and MMA(V) percentage were significantly positively associated and DMA(V) percentage was negatively associated with the risk of developmental delay in a dose-dependent manner after adjustment for blood lead or mercury levels and other risk factors. A multivariate regression analysis indicated that blood lead level and arsenic methylation capacity each independently contributed to the risk of developmental delay. This is the first study to show that arsenic methylation capacity is associated with developmental delay, even without obvious environmental arsenic exposure.

µLC-ICP-MS determinations of unexposed UK urinary arsenic speciation reference values.

This study provides background levels for five arsenic species in urine, based on urinary data obtained from 95 nonoccupationally exposed volunteers based in the UK. Using a novel, sensitive, robust and reliable speciation methodology, five species of arsenic (arsenobetaine [AB], arsenite [As(3+)], arsenate [As(5+)], monomethylarsonic acid [MMA(5+)] and dimethylarsinic acid [DMA(5+)]) were determined in urine samples collected from 95 adults. The analytical instrumentation used to analyze the urine samples was a hyphenated micro liquid chromatography (µLC) system coupled to an inductively coupled plasma mass spectrometry (ICP-MS). Separation was achieved using an anion exchange micro-sized column. The results presented give the 95th percentile of concentrations, both uncorrected for creatinine (µg/L) and creatinine corrected (µmol/mol) in urine for the 95 volunteers. Statistical analysis was performed on the dataset using a Bayesian model to determine and quantify effects of gender, smoking and diet. The statistical results show that the consumption of fish, shellfish and red wine has a significant elevating effect on AB, DMA and MMA urinary concentrations; however, no significant effect was observed for smoking. The regression model results indicate that creatinine correction was effective for arsenic species As(3+), MMA, DMA and AB. The background levels established here can be used as reference values to help aid interpretation of arsenic speciation results and better assess exposure.

Interaction effects of lead on bioavailability and pharmacokinetics of arsenic in the rat.

Arsenic (As) and lead (Pb) are common contaminants found in mine waste materials. For an evidence-based risk assessment, it is important to better understand the potential interaction of mixed contaminants; and this interaction study was investigated in an in vivo rat model. Following co-administration of a fixed dose of As(V) as in sodium arsenate and different doses of Pb as lead acetate to Sprague-Dawley rats, blood arsenic concentration and bioavailability decreased. A decrease in As blood concentration when lead was co-administered was observed with increasing lead doses. Pharmacokinetic parameters for As in the blood showed faster absorption and elimination of this metalloid in the presence of Pb. The elimination half-life of As decreased from 67 days in As solo group to 27-30 with doses of Pb. Bioavailability of As was also decreased by 30-43 % in the presence of Pb. Decreased urinary excretion of Pb and tissue accumulation were also observed. It indicates lower absorption of As when co-administered with Pb. A probable explanation for these findings is that As co-administration with Pb could have resulted in the formation of less soluble lead arsenate. However, such an interaction between As and Pb could only explain about one-third of the variation when real mine waste materials containing both of these elements were administered to rats. This suggests that other effects from physical and chemical parameters could contribute to the bioavailability of arsenic in complex real environmental samples.

Measurement of arsenic relative bioavailability in swine.

This study describes a method for measuring the relative oral bioavailability (RBA) of arsenic (As) in soil and other soil-like media using young swine as the animal model. Groups of animals are exposed to site soil or sodium arsenate orally for 12 d. Forty-eight-hour urine samples were collected from each animal on d 6-7, 8-9, and 10-11 and were analyzed for total As. The urinary excretion fraction (UEF) for each group was estimated by plotting the mass of As excreted in urine by each animal as a function of the dose administered, and then fitting a linear model to the data using simultaneous weighted linear regression. The RBA of a test material is calculated as the ratio of the UEF value for the test material divided by the UEF of the reference material. Uncertainty around the RBA estimate is calculated using Fieller's theorem. Application of this method to a series of test soils indicates that RBA values for As can range from 18 to 52%. This wide variability supports the conclusion that there may be important differences in RBA between sites, and that use of a site-specific RBA value is likely to increase the accuracy of risk estimates for exposure to As in soil.

Arsenic urinary speciation in Mthfr deficient mice injected with sodium arsenate.

In most mammalian species, arsenic biotransformation occurs primarily by biomethylation and reduction reactions, with dimethylarsinic acid being the predominant metabolite excreted in the urine. Methylenetetrahydrofolate reductase (Mthfr) plays a key role in folate metabolism by channeling one-carbon units between nucleotide synthesis and methylation reactions. In the study on transgenic Mtfhr knockout mice we investigated: (1) whether Mthfr is an important determinant in arsenic biotransformation by performing urinary arsenic speciation, and (2) whether dietary folate deficiency alters arsenic biotransformation in these mice. The Mthfr mice fed folate replete or folate deficient diet were injected with sodium arsenate 1mg/kg, and placed in metabolic cages for a urine collection. The urine was analyzed for arsenic species. Additionally, folate and homocysteine plasma level was analyzed in Mthfr mice. When fed a folate control diet, the Mthfr(-/-) mice excreted significantly less of the total arsenic in urine than did the Mthfr(+/+) and Mthfr(+/-) mice. The Mthfr(-/-) had significantly lower levels of pentavalent arsenic in their urine than did the Mthfr(+/+)mice. The wild type mice excreted significantly less pentavalent arsenic when they were fed folate deficient diet comparing to control diet. The current data suggest that both the Mthfr status and food folate level modulate in a significant manner excretion of arsenic in mice, following intraperitoneal administration of sodium arsenate.

Sequential extraction of inorganic arsenic compounds and methyl arsenate in human urine using mixed-mode monolithic silica spin column coupled with gas chromatography-mass spectrometry.

A sequential analytical method was developed for the detection of arsenite, arsenate, and methylarsenate in human urine by gas chromatography-mass spectrometry (GC-MS). The combination of a derivatization of trivalent arsenic compounds by 2,3-dithio-1-propanol (British antilewisite; BAL) and a reduction of pentavalent arsenic compounds (arsenate and methylarsenate) were accomplished to carry out the analysis of arsenic compounds in urine. The arsenic derivatives obtained using BAL were extracted in a stepwise manner using a monolithic spin column and analyzed by GC-MS. A linear curve was observed for concentrations of arsenic compounds of 2.0 to 200 ng/mL, where the correlation coefficients of calibration curves were greater than 0.996 (for a signal-to-noise (S/N) ratio >10). The detection limits were 1 ng/mL (S/N > 3). Recoveries of the targets in urine were in the range 91.9-106.5%, and RSDs of the intra- and interday assay for urine samples containing 5, 50, and 150 ng/mL of arsenic compounds varied between 2.95 and 13.4%. The results from real samples obtained from a patient suspected of having ingested As containing medications using this proposed method were in good agreement with those obtained using high-performance liquid chromatography with inductively coupled plasma mass spectrometry.

Altered arsenic disposition in experimental nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH.

Effects of co-administration of dietary sodium arsenate and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) on the rat bladder epithelium.

Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is metabolized to organic methylated arsenicals. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), a chelating agent, is capable of reducing pentavalent arsenicals to the trivalent state and binding to the trivalent species, and it has been used in the treatment of heavy metal poisoning in humans. Therefore, we investigated the ability of DMPS to inhibit the cytotoxicity and regenerative urothelial cell proliferation induced by arsenate administration in vivo. Female rats were treated for 4 weeks with 100 ppm As(V). DMPS (2800 ppm) co-administered in the diet significantly reduced the As(V)-induced cytotoxicity of superficial cells detected by scanning electron microscopy (SEM), and the incidence of simple hyperplasia observed by light microscopy and the bromodeoxyuridine (BrdU) labeling index. It also reduced the total concentration of arsenicals in the urine and the methylation of arsenic. There were no differences in oxidative stress as assessed by immunohistochemical staining for 8-hydroxy-2'-deoxyguanosine (8OHdG) of the bladder urothelium. No differences were detected in urine sediments between groups. These data suggest that DMPS has the ability to inhibit both arsenate-induced acute toxicity and regenerative proliferation of the rat bladder epithelium, most likely by decreasing exposure of the urothelium to trivalent arsenicals excreted in the urine. These data provide additional evidence that the effects of arsenate exposure in vivo do not appear to be related to oxidative effects on dG in DNA.