Analyses of micronuclei in exfoliated epithelial cells from individuals chronically exposed to arsenic via drinking water in inner Mongolia, China.

The groundwater in Bayingnormen (Ba Men), located in Central West Inner Mongolia, China, is naturally contaminated with arsenic at concentrations ranging from 50 microg/L to 1.8 mg/L. Various adverse health effects in this region, including cancer, have been linked to arsenic exposure via drinking water. A pilot study was undertaken to evaluate frequencies of micronuclei (MN), as measures of chromosomal alterations, in multiple exfoliated epithelial cell types from residents of Ba Men chronically exposed to arsenic via drinking water. Buccal mucosal cells, airway epithelial cells in sputum, and bladder urothelial cells were collected from 19 residents exposed to high levels of arsenic in drinking water (527.5 +/- 24 microg/l), and from 13 control residents exposed to relatively low levels of arsenic in drinking water (4.4 +/- microg/L). Analytical results from these individuals revealed that MN frequencies in the high-exposure group were significantly elevated to 3.4-fold over control levels for buccal and sputum cells, and to 2.7-fold over control for bladder cells (increases in MN frequency significant at p < .001 for buccal cells; p < .01 for sputum cells; p < .05 for bladder cells). When smokers were excluded from high-exposure and control groups the effects of arsenic were observed to be greater, although only in buccal and sputum cells; approximately 6-fold increases in MN frequency occurred in these tissues. The results indicate that residents of Ba Men chronically exposed to high levels of arsenic in drinking water reveal evidence of genotoxicity in multiple epithelial cell types; higher levels of induced MN were observed in buccal and sputum cells than in bladder cells.     

Micronuclei assessment in buccal cells of people environmentally exposed to arsenic in northern Chile

To determine the genotoxic risk associated to environmental arsenic exposure, the frequency of micronuclei in buccal cells (BCMN) of people drinking arsenic-contaminated water has been evaluated. A group of 105 individuals from the Antofagasta region (north Chile), and 102 individuals from the area of Concepcion, used as reference group, were included in the study. Arsenic concentration in drinking water was high (0.75 mg/L) in the Antofagasta area, 75-fold the maximum recommended level by WHO (0.01 mg/L), while the values obtained in Concepcion were significantly lower (0.002 mg/L). Individual measures of arsenic exposure were also determined in fingernails, which clearly confirm the existence of chronic exposure in the sampled populations from the Antofagasta region (10.15 microg/g versus 3.57 microg/g). The cytogenetic results indicate that, although the BCMN frequency is higher in exposed than in controls, this increase does not attain statistical significance. When the exposure biomarkers were related with the cytogenetic values, no correlations were observed between BCMN and arsenic content in water or in fingernails. In addition, the genotoxicity values do not seem to be related to the ethnic origin from people belonging to the exposed group. As a conclusion it appears that, in the studied population, the chronic ingestion of arsenic-contaminated water does not induce cytogenetic damage, measured as micronuclei, in the cells of the oral mucous in a significant extent.     

DNA repair gene XPD and susceptibility to arsenic-induced hyperkeratosis

Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. An estimated 50-70 million people in Bangladesh have been chronically exposed to arsenic from drinking water and are at risk of skin and other cancers. We undertook the first study to examine whether genetic susceptibility, as determined by the codon 751 SNP (A-->C) of the DNA repair gene XPD, influences the risk of arsenic-induced hyperkeratotic skin lesions, precursors of skin cancer, in a case-control study of 29 hyperkeratosis cases and 105 healthy controls from the same community in an area of Bangladesh. As expected, there was a monotonic increase in risk of hyperkeratosis in relation to urinary arsenic measures but the XPD genotype was not independently associated with the risk. However, the increase in hyperkeratosis risk in relation to urinary arsenic measures genotype was borderline significant for urinary total arsenic (P for trend=0.06) and statistically significant for urinary creatinine adjusted arsenic (P for trend=0.01) among subjects with the XPD A allele (AA) but not among subjects with the other XPD genotypes. Among AA carriers, the risk for the highest arsenic exposed group compared with the lowest was more than 7-fold for urinary total arsenic and about 11-fold for urinary creatinine adjusted arsenic. In conclusion, our findings suggest that the DNA repair gene XPD may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions. Future larger studies are needed to confirm this novel finding and investigate how combinations of different candidate genes and/or other host and environmental factors may influence the risk of arsenic induced skin and other cancers.     

Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells

Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.     

Bladder/lung cancer mortality in Blackfoot-disease (BFD)-endemic area villages with low (<150 μg/L) well water arsenic levels – An exploration of the dose–response Poisson analysis

ObjectiveTo examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 μg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data.MethodPoisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (μg/kg/day) for the low-dose (<150 μg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data.ResultsUse of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 μg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors.ConclusionThe cancer rates are higher among the low-dose (<150 μg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.     

Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

Abstract

The biologic effects of inorganic arsenic predominantly involve reaction of the trivalent forms with sulfhydryl groups in critical proteins in target cells, potentially leading to various toxicologic events including cancer. This mode of action is a threshold process, requiring sufficient concentrations of trivalent arsenic to disrupt normal cellular function. Nevertheless, cancer risk assessments for inorganic arsenic have traditionally utilized various dose-response models that extrapolate risks from high doses assuming low-dose linearity without a threshold. We present here an approach for a cancer risk assessment for inorganic arsenic in drinking water that involves considerations of this threshold process. Extensive investigations in mode of action analysis, in vitro studies (>0.1?µM), and in animal studies (>2?mg/L in drinking water or 2?mg/kg of diet), collectively indicate a threshold basis for inorganic arsenic-related cancers. These studies support a threshold for the effects of arsenic in humans of 50–100?µg/L in drinking water (about 65?µg/L). We then evaluate the epidemiology of cancers of the urinary bladder, lung, and skin and non-cancer skin changes for consistency with this calculated value, focusing on studies involving low-level exposures to inorganic arsenic primarily in drinking water (approximately <150?µg/L). Based on the relevant epidemiological studies with individual-level data, a threshold level for inorganic arsenic in the drinking water for these cancers is estimated to be around 100?µg/L, with strong evidence that it is between 50 and 150?µg/L, consistent with the value calculated based on mechanistic, in vitro and in vivo investigations. This evaluation provides an alternative mode of action-based approach for assessing health-protective levels for oral arsenic exposure based on the collective in vitro, in vivo, and human evidence rather than the use of a linear low-dose extrapolation based on default assumptions and theories.     

Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., < 200 μg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99–3.67), and 3.26 (1.76–6.04) (p-trend < 0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06–3.11), and 2.02 (1.15–3.54) (p-trend < 0.001). In analyses confined to subjects only with arsenic water concentrations < 200 μg/L (median = 60 μg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08–5.68) and 2.37 (1.01–5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations.     

Smoking habit and genetic factors associated with lung cancer in a population highly exposed to arsenic

In order to find some relationship between genetic differences in metabolic activation and detoxification of environmental carcinogens and host susceptibility to chemically induced cancers, we have investigated the distribution of the GSTM1 null genotype and CYP450 *1A1 MspI polymorphism in lung cancer patients and healthy volunteers of the second region in the north of Chile highly exposed to arsenic. The main sources of environmental arsenic exposure in Chile are copper smelting and drinking water, specially in the second region, the most important copper mining region in the world that shows the highest lung cancer mortality rate in the country (35/100.00). The population of Antofagasta, the main city of the region was exposed between 1958 and 1970 to arsenic concentrations in drinking water of 860 microg/m3, presently declining to 40 microg/m3. For men the MspI CYP1A1 *2A genotype was associated with a highly significant estimated relative lung cancer risk (O.R. = 2.60), but not GSTM1 by itself. The relative lung cancer risk for the combined 2A/null GSTM1 genotypes was 2.51, which increased with the smoking habits (O.R. = 2.98). In the second region the cancer mortality rate for As associated cancers, might be related at least part to differences in As biotransformation. In this work we demonstrate that genetic biomarkers such as CYP1A1 2A and GSTM1 polymorphisms in addition to DR70 as screening biomarkers might provide relevant information to identify individuals with higher risk for lung cancer, due to arsenic exposure.     

Apoptosis of peripheral blood mononuclear cells in children exposed to arsenic and fluoride

In this study, we evaluated apoptosis induction in human immune cells in children exposed to arsenic (As) and fluoride (F). Children living in two areas in Mexico (Soledad de Graciano Sanchez (SGS) in San Luis Potosí and Colonia 5 de Febrero in Durango) were studied. Water, urine and blood samples were collected. Approximately 90% of the water samples in 5 de Febrero had As and F levels above the World Health Organization intervention guideline (10 μg/L and 1.5mg/L, respectively). In SGS, 0% of the water samples exceeded Mexican guidelines. Urinary As and F levels in children living in 5 de Febrero were significantly higher than the levels found in children living in SGS. In addition, the level of apoptosis was higher in children from the 5 de Febrero community when compared with the level of apoptosis in children living in SGS. Thus, in a worldwide context, our study demonstrates the health risks to children living in these regions.     

Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic

Monomethylarsonous acid (MMA(III)) has been detected for the first time in the urine of some humans exposed to inorganic arsenic in their drinking water. Our experiments have dealt with subjects in Romania who have been exposed to 2.8, 29, 84, or 161 microg of As/L in their drinking water. In the latter two groups, MMA(III) was 11 and 7% of the urinary arsenic while the monomethylarsonic acid (MMA(V)) was 14 and 13%, respectively. Of our 58 subjects, 17% had MMA(III) in their urine. MMA(III) was not found in urine of any members of the group with the lowest level of As exposure. If the lowest-level As exposure group is excluded, 23% of our subjects had MMA(III) in their urine. Our results indicate that (a) future studies concerning urinary arsenic profiles of arsenic-exposed humans must determine MMA(III) concentrations, (b) previous studies of urinary profiles dealing with humans exposed to arsenic need to be re-examined and re-evaluated, and (c) since MMA(III) is more toxic than inorganic arsenite, a re-examination is needed of the two hypotheses which hold that methylation is a detoxication process for inorganic arsenite and that inorganic arsenite is the major cause of the toxicity and carcinogenicity of inorganic arsenic.     

Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review

Chronic arsenic (As) poisoning has become a worldwide public health issue. Most human As exposure occurs from consumption of drinking water containing high amounts of inorganic As (iAs). In this paper, epidemiological studies conducted on the dose-response relationships between iAs exposure via the drinking water and related adverse health effects are reviewed. Before the review, the methods for evaluation of the individual As exposure are summarized and classified into two types, that is, the methods depending on As concentration of the drinking water and the methods depending on biological monitoring for As exposure; certain methods may be applied as optimum As exposure indexes to study dose-response relationship based on various As exposure situation. Chronic effects of iAs exposure via drinking water include skin lesions, neurological effects, hypertension, peripheral vascular disease, cardiovascular disease, respiratory disease, diabetes mellitus, and malignancies including skin cancer. The skin is quite sensitive to arsenic, and skin lesions are some of the most common and earliest nonmalignant effects related to chronic As exposure. The increase of prevalence in the skin lesions has been observed even at the exposure levels in the range of 0.005-0.01 mg/l As in drinking waters. Skin, lung, bladder, kidney, liver, and uterus are considered as sites As-induced malignancies, and the skin is though to be perhaps the most sensitive site. Prospective studies in large area of endemic As poisoning, like Bangladesh or China, where the rate of malignancies is expected to increase within the next several decades, will help to clarify the dose-response relationship between As exposure levels and adverse health effects with enhanced accuracy.     

CYP1A1 and GSTM1 genetic polymorphisms in lung cancer populations exposed to arsenic in drinking water

Region II of Chile is the most important copper mining area in the world and it shows the highest lung cancer mortality rate in the country (35/100?000). The population in Antofagasta, the main city of Region II, was exposed from 1958 to 1970 to 860?µg?m^?3 arsenic (As) in drinking water and has currently been declining to 40?µg?m^?3. Glutathione serves as a reducing agent and glutathione S-transferase (GST) may have an important role in As methylation capacity and body retention. In the current study, the null genotype of GSTM1 and the MspI polymorphism of CYP450 1A1 were investigated in lung cancer patients and in healthy volunteers of Region II. In males, the 2A genotype of MspI represented a highly significant estimated relative lung cancer risk (OR?=?2.60). Relative lung cancer risk for the combined 2A/null GSTM1 genotypes was 2.51, which increased with the smoking habit (OR?=?2.98). In Region II, the cancer mortality rate for As-associated cancers at least partly might be related to differences in As biotransformation. Genetic biomarkers such as 2A and GSTM1 polymorphisms in addition to DR70 as screening biomarkers might provide relevant information to identify individuals with a high risk for lung cancer as prevention and protection actions to protect public health.     

Selected markers of cardiovascular disease in a population exposed to arsenic from drinking water

This study examined prevalence and serum levels of selected markers of cardiovascular disease in 34 subjects from a Croatian rural population exposed to high levels of arsenic (As) from drinking water (611.89±10.06μg/l). The prevalences of overweight and obese subjects in the population were 32% and 35%. Half the subjects had hypertension, 29% had increased fasting serum glucose level and two were diabetic. Median total cholesterol (5.82mmol/l) and triglycerides (2.15mmol/l) were above the desirable margins. The median C-reactive protein level (1.20mg/l) was slightly higher than previously reported for healthy subjects. Serum Hsp70 level was significantly higher in nonsmokers. Total urinary As levels were positively correlated with age-adjusted serum levels of cobalamin. Near significance were also serum total bilirubin, antibodies to Hsp60 and folate. Tentative investigation of risk factors among subjects classified by tumor necrosis factor-α -308G/A and interleukin-6-174G/C gene polymorphisms was also performed. Collectively, the results are in agreement with the hypothesis of As-induced and/or compounded cardiovascular disease.     

Toxicological effects and bioaccumulation in the freshwater clam (Corbicula fluminea) following exposure to trivalent arsenic

Contamination of aquatic environments by arsenic is a serious worldwide problem. The main objective of this work was to evaluate the response of a freshwater clam (Corbicula fluminea) to arsenic (As III) exposure and infer its potential as a biological indicator of contamination. Metallothioneins (MTs) were used as indicators of metalloid toxicity in combination with an histological and histochemical evaluation. After a period of acclimatization in the laboratory, 50 C. fluminea (0.4 g +/- 0.1) were exposed to different nominal concentrations of arsenic (100, 300, 500, and 1000 microg L(-1)) for 7 days. The concentration of total As III in the water and in the tissues of the organisms was determined by atomic absorption spectrometry, and MTs were quantified through differential pulse polarography. Results suggest that the organisms exposed to the concentrations of 300 and 1000 microg As L(-1) accumulated the highest levels of As III in the tissues (17 +/- 9 and 15 +/- 3 microg g(-1) distilled water, respectively), which was confirmed through histochemical analysis. An apparent induction of MTs was also observed in the organisms exposed to As III, suggesting that C. fluminea possesses some capacity for arsenic regulation. The results suggest that the induction of MTs may be of high interest as a biomarker for arsenic contamination in aquatic environments, and confirms the potential of C. fluminea as a biological indicator.     

Associations of arsenic metabolites,methylation capacity,and skin lesions caused by chronic exposure to high arsenic in tube well water

To investigate the interaction between skin lesion status and arsenic methylation profiles, the concentrations and proportions of arsenic metabolites in urine and arsenic methylation capacities of study subjects were determined. The results showed that the mean urinary concentrations of iAs (inorganic arsenic), MMA (monomethylarsonic acid), DMA (dimethylarsinic acid), and TAs (total arsenic) were 75.65, 68.78, 265.81, and 410.24 μg/L, respectively, in the skin lesions subjects. The highest values were observed in the multiple skin lesions subjects. Higher %iAs and %MMA, and lower %DMA, PMI (primary methylation index), and SMI (secondary methylation index) were found in skin lesions subjects. The multiple skin lesions subjects had highest %iAs and %MMA, and lowest %DMA, PMI, and SMI. The prevalence of skin lesions strongly, positively correlated with arsenic levels in drinking water. The elder persons also had higher frequency of skin lesions compared with younger persons. It can be concluded that arsenic levels in drinking water significantly affected the prevalence of skin lesions. Male subjects usually had higher proportions of skin lesions when compared with female subjects. Moreover, it may be concluded that MMA was significantly related to single skin lesion, whereas DMA and iAs were associated with multiple skin lesions. It seemed that MMA had greater toxicity to hyperkeratosis, whereas DMA and iAs had higher toxicity to depigmentation or pigmentation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 28–36, 2017.     

Arsenic exposure induces genomic hypermethylation

Gene‐specific hypermethylation has previously been detected in Arsenic exposed persons. To monitor the level of whole genome methylation in persons exposed to different levels of Arsenic via drinking water, DNA was extracted from peripheral blood mononuclear cells of 64 persons. Uptake of methyl group from ³H labeled S‐Adenosyl Methionine after incubation of DNA with SssI methylase was measured. Results showed statistically significant (P = 0.0004) decrease in uptake of ³H methyl group in the persons exposed to 250–500 μg/L arsenic, indicating genomic hypermethylation. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

In utero and early childhood exposure to arsenic decreases lung function in children

The lung is a target organ for adverse health outcomes following exposure to As. Several studies have reported a high prevalence of respiratory symptoms and diseases in subjects highly exposed to As through drinking water; however, most studies to date has been performed in exposed adults, with little information on respiratory effects in children. The objective of the study was to evaluate the association between urinary levels of As and its metabolites with lung function in children exposed in utero and in early childhood to high As levels through drinking water. A total of 358 healthy children were included in our study. Individual exposure was assessed based on urinary concentration of inorganic As. Lung function was assessed by spirometry. Participants were exposed since pregnancy until early childhood to an average water As concentration of 152.13 µg l^–1. The mean urinary As level registered in the studied subjects was 141.2 µg l^–1 and only 16.7% had a urinary concentration below the national concern level. Forced vital capacity was significantly decreased in the studied population and it was negatively associated with the percentage of inorganic As. More than 57% of the subjects had a restrictive spirometric pattern. The urinary As level was higher in those children with restrictive lung patterns when compared with the levels registered in subjects with normal spirometric patterns. Exposure to As through drinking water during in utero and early life was associated with a decrease in forced vital capacity and with a restrictive spirometric pattern in the children evaluated. Copyright © 2014 John Wiley & Sons, Ltd.     

Neurosensory effects of chronic human exposure to arsenic associated with body burden and environmental measures

Exposure to arsenic in drinking water is known to produce a variety of health problems, including peripheral neuropathy. Auditory, visual and somatosensory impairment have been reported in Mongolian farmers living in the Yellow River Valley, where drinking water is contaminated by arsenic. In the present study, sensory tests, including pinprick and vibration thresholds, were administered to 320 residents with well-water arsenic levels, ranging from non-detectable to 690 microg/L. Vibration thresholds in the second and fifth fingers of both hands were measured using a vibrothesiometer. Drinking water, urine and toenail samples were obtained to assess arsenic exposure and body burden. Regression analyses indicated significant associations of pinprick scores and vibration thresholds with all arsenic measures. Vibration thresholds were more strongly associated with urinary than water or nail arsenic measures, but odds ratios for decreased pinprick sensitivity were highest for the water arsenic measure. Results of the current study indicate neurosensory effects of arsenic exposure at concentrations well below the 1000 microg/L drinking water level specified by NRC, and suggest that non-carcinogenic end-points, such as vibration thresholds, are useful in the risk assessment of exposure to arsenic in drinking water.     

Increased hexokinase II expression in the renal glomerulus of mice in response to arsenic

Epidemiological studies link arsenic exposure to increased risks of cancers of the skin, kidney, lung, bladder and liver. Additionally, a variety of non-cancerous conditions such as diabetes mellitus, hypertension, and cardiovascular disease have been associated with chronic ingestion of low levels of arsenic. However, the biological and molecular mechanisms by which arsenic exerts its effects remain elusive. Here we report increased renal hexokinase II (HKII) expression in response to arsenic exposure both in vivo and in vitro. In our model, HKII was up-regulated in the renal glomeruli of mice exposed to low levels of arsenic (10 ppb or 50 ppb) via their drinking water for up to 21 days. Additionally, a similar effect was observed in cultured renal mesangial cells exposed to arsenic. This correlation between our in vivo and in vitro data provides further evidence for a direct link between altered renal HKII expression and arsenic exposure. Thus, our data suggest that alterations in renal HKII expression may be involved in arsenic-induced pathological conditions involving the kidney. More importantly, these results were obtained using environmentally relevant arsenic concentrations.