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Background: Arsenic exposure through drinking water is an established lung carcinogen. Evidence on non-malignant lung outcomes is less conclusive and suggests arsenic is associated with lower lung function. Studies examining low-moderate arsenic (< 50 μg/L), the level relevant for most populations, are limited. We evaluated the association of arsenic exposure with respiratory health in American Indians from the Northern Plains, the Southern Plains and the Southwest United States, communities with environmental exposure to inorganic arsenic through drinking water., Methods: The Strong Heart Study is a prospective study of American Indian adults. This analysis used urinary arsenic measurements at baseline (1989-1991) and spirometry at Visit 2 (1993-1995) from 2132 participants to evaluate associations of arsenic exposure with airflow obstruction, restrictive pattern, self-reported respiratory disease, and symptoms., Results: Airflow obstruction was present in 21.5% and restrictive pattern was present in 14.4%. The odds ratio (95% confidence interval) for obstruction and restrictive patterns, based on the fixed ratio definition, comparing the 75th to 25th percentile of arsenic, was 1.17 (0.99, 1.38) and 1.27 (1.01, 1.60), respectively, after adjustments, and 1.28 (1.02, 1.60) and 1.33 (0.90, 1.50), respectively, based on the lower limit of normal definition. Arsenic was associated with lower percent predicted FEV1 and FVC, self-reported emphysema and stopping for breath., Conclusion: Low-moderate arsenic exposure was positively associated with restrictive pattern, airflow obstruction, lower lung function, self-reported emphysema and stopping for breath, independent of smoking and other lung disease risk factors. Findings suggest that low-moderate arsenic exposure may contribute to restrictive lung disease.

Arsenic (As) speciation and bioaccumulation in fish muscle tissues have been intensively investigated in marine ecosystem. However, little is known about these in freshwater fish. In this study, freshwater fish including 120 specimens and 8 species were collected from the Xiang River, a typical mine-impacted river in China. Six As species including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), arsenocholine (AsC) and arsenobetaine (AsB) were simultaneously separated and determined using HPLC-ICP-MS. The mean (±SD) concentration of total As (tAs) in the dried fish muscle was 0.748±0.651mg·kg -1 . AsB was found as the predominant As species in most of the studied fish samples, in accordance with the reports in marine fish. However, the diversity of inorganic/organic As proportion observed in the studied freshwater fish species was larger than that in marine fish species due to greater spatial variability of As contamination, mobilization and origination in the studied catchments. The percentage of AsB (AsB%) in fish muscle was irrelevant to tAs concentration, while the percentage of iAs (iAs%) decreased with tAs concentration in a hyperbolic pattern. This can be attributed to restricted assimilation and accumulation of toxic iAs with increasing tAs concentration in fish. Chronic non-carcinogenic and carcinogenic health risks were evaluated through Monte-Carlo simulation. The result indicated that consuming freshwater fish in the Xiang River could cause considerable carcinogenic risk to local inhabitants., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Exposure to organophosphorus nerve agents, the most deadly chemical warfare agents, is possible in a variety of situations, such as destruction of chemical warfare agents, terrorist attacks, armed conflicts or accidents in research laboratories and storage facilities. Hundreds of thousands of tons of chemical munitions were disposed of at the sea in the post World War II period, with European, Russian, Japanese and US coasts being the most affected. Sulfur mustard, Lewisite and nerve agents appear to be the most frequently chemical warfare agents disposed of at the sea. Addressing the overall environmental risk, it has been one of the priorities of the world community since that time. Aside from confirming exposure to nerve agents in the alleged use for forensic purposes, the detection and identification of biological markers of exposure are also needed for the diagnosis and treatment of poisoning, in addition to occupational health monitoring for specific profiles of workers. When estimating detrimental effects of acute or potential chronic sub-lethal doses of organophosphorus nerve agents, released accidentally or intentionally into the environment, it is necessary to understand the wide spectra of physical, chemical and toxicological properties of these agents, and predict their ultimate fate in environmental systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Diphenylarsinic acid (DPAA), a neurotoxic organic arsenical used as a chemical warfare agent, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. We previously demonstrated that DPAA promotes diethylnitrosamine-induced liver carcinogenesis in a medium-term rat liver bioassay. The purpose of the present study was to evaluate the potential carcinogenicity of DPAA, including investigation of whether the bile duct hyperplasia in the liver that was observed in a previous 52 week rat chronic study develops into a tumor, when administered to rats in their drinking water for 104 weeks. DPAA was administered to groups 1-4 at concentrations of 0, 5, 10, and 20 ppm in their drinking water for 104 weeks. A significant decrease in survival rate was found for females in the 20 ppm DPAA group. Body weights of males in the 20 ppm and females in the 10 and 20 ppm DPAA groups were significantly decreased compared to the controls. Overall histopathological evaluation of neoplasms in all tissues showed no significant increase of tumor incidence in any organ or tissue of the 5, 10, or 20 ppm DPAA-treated male or female F344 rats. In conclusion, the present study demonstrated that DPAA is not a complete carcinogen in male or female F344 rats.

Background and Aims: Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality., Methods: Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty-four percent to 96 % of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry., Results: Nail arsenic levels were raised in five (10 %) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11 %) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5 μg/L)., Conclusions: Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'.

Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Although some studies mainly from Taiwan, Bangladesh and the United States, have suggested a consistent dose-response increase in the prevalence of hypertension with increasing arsenic exposure, the association between chronic environmental arsenic exposure and the risk of hypertension is still inconclusive. Most of the studies discussed the association from the point of view of arsenic concentration in drinking water or cumulative arsenic exposure (CAE), few involved arsenic speciation into the discussion. In this cross-sectional study, we evaluated the potential association between environmental arsenic exposure through drinking water and the prevalence of hypertension by analyzing not only CAE but also urinary arsenic speciation, and provided data on arsenic exposure and hypertension from mainland of China., Methods: A cross-sectional study was conducted in one of the arsenic contaminated areas in the northwest of China. Among a total of 1005 residents who voluntarily participated in the study, 604 of eligible subjects were confirmed and interviewed door to door. Standing height, body weight, and blood pressure were measured. First void urine was collected and measured for the concentration of urinary arsenic speciation. CAE was calculated in a subpopulation of 360 subjects with detailed water consumption history. The association between urinary arsenic speciation, CAE and the risk of hypertension were analyzed by multiple logistic regressions., Results: We found that the levels of urinary arsenic species of inorganic arsenic (iAs), monomethylated arsenic (MMA), dimethylated arsenic (DMA) and total arsenic (tAs) were significantly correlated with systolic or pulse blood pressure. A positive relationship was found between the highest tertile of CAE and hypertension in a dose-dependent manner. Subjects with higher concentration of urinary MMA or lower percentage of DMA tended to be liable to suffer from hypertension. A significant increasing trend of the risk of hypertension with increasing tertiles of MMA concentration was also observed in the logistic regression models both before and after adjustment for confounders., Conclusions: Our findings suggested that arsenic exposure, especially high level of CAE, was positively associated with the prevalence of hypertension, and that higher concentration of urinary MMA might be related to the increased susceptibility to hypertension.

Sixty-four arsenic (As) resistant bacteria isolated from an arsenic rich groundwater sample of West Bengal were characterized to investigate their potential role in subsurface arsenic mobilization. Among the isolated strains predominance of genera Agrobacterium/Rhizobium, Ochrobactrum and Achromobacter which could grow chemolitrophically and utilize arsenic as electron donor were detected. Higher tolerance to As(3+) [maximum tolerable concentration (MTC): ≥10 mM], As(5+) (MTC: ≥100 mM) and other heavy metals like Cu(2+), Cr(2+), Ni(2+) etc. (MTC: ≥10 mM), presence of arsenate reductase and siderophore was frequently observed among the isolates. Ability to produce arsenite oxidase and phosphatase enzyme was detected in 50 and 34 % of the isolates, respectively. Although no direct correlation among taxonomic identity of bacterial strains and their metabolic abilities as mentioned above was apparent, several isolates affiliated to genera Ochrobactrum, Achromobacter and unclassified Rhizobiaceae members were found to be highly resistant to As(3+) and As(5+) and positive for all the test properties. Arsenate reductase activity was found to be conferred by arsC gene, which in many strains was coupled with arsenite efflux gene arsB as well. Phylogenetic incongruence between the 16S rRNA and ars genes lineages indicated possible incidence of horizontal gene transfer for ars genes. Based on the results we propose that under the prevailing low nutrient condition inhabitant bacteria capable of using inorganic electron donors play a synergistic role wherein siderophores and phosphatase activities facilitate the release of sediment bound As(5+), which is subsequently reduced by arsenate reductase resulting into the mobilization of As(3+) in groundwater.

The accumulation, subcellular distribution and speciation of arsenic in the polychaete Arenicola marina were investigated under different laboratory exposure conditions representing a range of metal bioavailabilities, to gain an insight into the physiological mechanisms of how A. marina handles bioaccumulated arsenic and to improve our understanding of the potential ecotoxicological significance of bioaccumulated arsenic in this deposit-feeder. The exposure conditions included exposure to sublethal concentrations of dissolved arsenate, exposure to sublethal concentrations of sediment-bound metal mining mixtures, and exposure to lethal concentrations of sediment-bound metal mining mixtures and arsenic- and multiple metal-spiked sediments. The sub-lethal exposures indicate that arsenic bioaccumulated by the deposit-feeding polychaete A. marina is stored in the cytosol as heat stable proteins (~50%) including metallothioneins, possibly as As (III)-thiol complexes. The remaining arsenic is mainly accumulated in the fraction containing cellular debris (~20%), with decreasing proportions accumulated in the metal-rich granules, organelles and heat-sensitive proteins fractions. A biological detoxified metal compartment including heat stable proteins and the fraction containing metal-rich granules is capable of binding arsenic coming into the cells at a constant rate under sublethal arsenic bioavailabilities. The remaining arsenic entering the cell is bound loosely into the cellular debris fraction, which can be subsequently released and diverted to an expanding detoxified pool. Our results suggest that a metal sensitive compartment comprising the cellular debris, enzymes and organelles fractions may be more representative of the toxic effects observed.

It is well known that oxidative damage plays a key role in the development of chronic arsenicosis. There is a complex set of mechanisms of redox cycling in vivo to protect cells from the damage. In this study, we examined the differences in the levels of serum thioredoxin1 (TRX1) among individuals exposed to different levels of arsenic in drinking water and detected early biomarkers of arsenic poisoning before the appearance of skin lesions. A total of 157 subjects from endemic regions of China were selected and divided into arsenicosis group with skin lesions (total intake of arsenic: 8.68-45.71mg-year) and non-arsenicosis group without skin lesions, which further divided into low (0.00-1.06mg-year), medium (1.37-3.55mg-year), and high (4.26-48.13mg-year) arsenic exposure groups. Concentrations of serum TRX1 were analyzed by an ELISA method. Levels of water arsenic and urinary speciated arsenics, including inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA), were determined by hydride generation atomic absorption spectrometry. Our results showed that the levels of serum TRX1 in arsenicosis patients were significantly higher than that of the subjects who were chronically exposed to arsenic, but without skin lesions. A positive correlation was seen between the levels of serum TRX1 and the total water arsenic intake or the levels of urinary arsenic species. The results of this study indicate that arsenic exposure could significantly change the levels of human serum TRX1, which can be detected before arsenic-specific dermatological symptoms occur. This study provides further evidence on revealing the mechanism of arsenic toxicity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Citizens in an area of Kamisu City, Ibaraki, Japan had exhibited unusual health problems, and pollution of well water by diphenylarsinic acid (DPAA) was found in the area. We examined the effects of DPAA on various behaviors in mice. DPAA was administered to mice through free intake of drinking water for 27 weeks (subchronic exposure) or 57 weeks (chronic exposure), and behavior was examined during exposure. DPAA at 30-100 ppm increased ambulatory activity and the response rate of the shuttle type discrete conditioned avoidance response of mice. DPAA reduced coordination ability on the fixed rod at 100 ppm. DPAA at 7.5-15 ppm also reduced coordination on the rotating rod, although these doses of DPAA did not affect coordination on the fixed rod. Chronic exposure to 7.5-15 ppm of DPAA produced anti-anxiety-like effects in the elevated plus maze test, whereas subchronic exposure to 100 ppm of DPAA produced anxiogenic-like effects. Neither subchronic nor chronic exposure to 7.5-100 ppm of DPAA affected learning ability and/or memory, as evaluated using the passive avoidance response. Exposure to 15-30 ppm of DPAA for 52 weeks did not alter weights of the cerebrum and cerebellum or amounts of neuron marker protein TUJ-1 or astrocyte marker protein glial fibrillary acidic protein in the cerebellum of mice. Behavioral effects observed in mice seem relevant to symptoms observed in patients from Kamisu City., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The investigated data indicated that inorganic arsenic in drinking water is associated with increased mortality from different types of cancers. In the present study, biological samples (blood and scalp hair) of male subjects having lung and bladder cancers and non-cancerous subjects belonging to arsenic (As)-exposed area of southern parts of Pakistan were analysed for As contents. The As levels in drinking water of understudy area showed that sections of understudy population are exposed to arsenic concentrations, which was 3-15-fold higher than the permissible level (<10 μg/L). For comparative purposes the biological samples of matched male cancer patient, as referent patients belonging to big city (Hyderabad) who had used municipal treated water with low arsenic levels <10 μg/L, were also collected. The exposed cancer patients have 2-3-fold higher level of As in both biological samples compared to non-exposed case-matched cancerous male subjects. This study is compelling evidence in support of positive associations between arsenic-contaminated water, food and cigarette with different types of risks of cancer.

That chemical insults or nutritive changes during in utero and/or postnatal life can emerge as diseases much later in life are now being accepted as a recurring phenomenon. In this regard, inorganic arsenic is a multisite human carcinogen found at high levels in the drinking water of millions of people, although it has been difficult until recently to produce tumors in rodents with this metalloid. A mouse transplacental model has been developed where maternal exposure to inorganic arsenic either acts as a complete carcinogen or enhances carcinogenic response to other agents given subsequently in the offspring, producing tumors during adulthood. Similarly, human data now have emerged showing that arsenic exposure during the in utero period and/or in early life is associated with cancer in adulthood. The mouse arsenic transplacental model produces tumors or enhances response to other agents in multiple strains and tissues, including sites concordant with human targets of arsenic carcinogenesis. It is now believed that cancer often is a stem cell (SC)-based disease, and there is no reason to think cancer induced by developmental chemical exposure is any different. Indeed, arsenic impacts human SC population dynamics in vitro by blocking exit into differentiation pathways and whereby creating more key targets for transformation. In fact, during in vitro malignant transformation, arsenic causes a remarkable survival selection of SCs, creating a marked overabundance of cancer SCs (CSCs) compared with other carcinogens once a cancer phenotype is obtained. In addition, skin cancers produced following in utero arsenic exposure in mice are highly enriched in CSCs. Thus, arsenic impacts key, long-lived SC populations as critical targets to cause or facilitate later oncogenic events in adulthood as a possible mechanism of developmental basis of adult disease.

As part of our efforts to identify effective ways and means to keep source water safe, the concept of risk assessment and management is introduced in this paper to address the issue of risk assessment and management of arsenic in source water in China. Carcinogenic and non-carcinogenic risk are calculated for different concentrations of arsenic in source water using the corrective equation between potential health risk and concentration of arsenic in source water with purification process taken into consideration. It is justified through analyses that risk assessment and management is suitable for China to control pollution of source water. The permissible content of arsenic in source water should be set at 0.01 mg/L at present in China, and necessary risk management measures include control contaminated sources and improvement of purification efficiency.

A 42-year-old man presented with a six-month history of a slowly-enlarging ulcer on his right sole, a 30-year history of altered pigmentation of the trunk and extremities, and hyperkeratotic papules of the palms and soles. Histopathologic examination showed an invasive squamous-cell carcinoma of the right sole and hyperkeratosis with keratinocyte atypia of the left finger and left lateral foot. The clinical and histopathologic findings are consistent with chronic arsenicism, which most commonly occurs in the setting of drinking contaminated water or after occupational exposure. Evaluation should include a physical examination, basic laboratory work-up, and measurement of a 24-hour urine arsenic concentration. Vigilant surveillance for the development of cutaneous malignancies is required. Oral retinoids may be helpful in reducing hyperkeratosis secondary to chronic arsenicism.

This study spatially analyzed potential carcinogenic risks associated with ingesting arsenic (As) contents in aquacultural smeltfish (Plecoglossus altirelis) from the Lanyang Plain of northeastern Taiwan. Sequential indicator simulation (SIS) was adopted to reproduce As exposure distributions in groundwater based on their three-dimensional variability. A target cancer risk (TR) associated with ingesting As in aquacultural smeltfish was employed to evaluate the potential risk to human health. The probabilistic risk assessment determined by Monte Carlo simulation and SIS is used to propagate properly the uncertainty of parameters. Safe and hazardous aquacultural regions were mapped to elucidate the safety of groundwater use. The TRs determined from the risks at the 95th percentiles exceed one millionth, indicating that ingesting smeltfish that are farmed in the highly As-affected regions represents a potential cancer threat to human health. The 95th percentile of TRs is considered in formulating a strategy for the aquacultural use of groundwater in the preliminary stage.

We studied the bioavailability and toxicity of copper, zinc, arsenic, cadmium, and lead in sediments from Lake Roosevelt (LR), a reservoir on the Columbia River in Washington, USA that receives inputs of metals from an upstream smelter facility. We characterized chronic sediment toxicity, metal bioaccumulation, and metal concentrations in sediment and pore water from eight study sites: one site upstream in the Columbia River, six sites in the reservoir, and a reference site in an uncontaminated tributary. Total recoverable metal concentrations in LR sediments generally decreased from upstream to downstream in the study area, but sediments from two sites in the reservoir had metal concentrations much lower than adjacent reservoir sites and similar to the reference site, apparently due to erosion of uncontaminated bank soils. Concentrations of acid-volatile sulfide in LR sediments were too low to provide strong controls on metal bioavailability, and selective sediment extractions indicated that metals in most LR sediments were primarily associated with iron and manganese oxides. Oligochaetes (Lumbriculus variegatus) accumulated greatest concentrations of copper from the river sediment, and greatest concentrations of arsenic, cadmium, and lead from reservoir sediments. Chronic toxic effects on amphipods (Hyalella azteca; reduced survival) and midge larvae (Chironomus dilutus; reduced growth) in whole-sediment exposures were generally consistent with predictions of metal toxicity based on empirical and equilibrium partitioning-based sediment quality guidelines. Elevated metal concentrations in pore waters of some LR sediments suggested that metals released from iron and manganese oxides under anoxic conditions contributed to metal bioaccumulation and toxicity. Results of both chemical and biological assays indicate that metals in sediments from both riverine and reservoir habitats of Lake Roosevelt are available to benthic invertebrates. These findings will be used as part of an ongoing ecological risk assessment to determine remedial actions for contaminated sediments in Lake Roosevelt.

It has been clinically reported that chronic exposure to diphenylarsinic acid (DPAA) induced prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The aim of the present study was then to investigate the effect of chronic treatment with DPAA on the central motor impairment in mice. In the present study, we found that chronic in vivo exposure to a high dose of DPAA induced motor impairment in adult mice. This impairment was reversed by withdrawal following chronic DPAA treatment. The [35S]GTPgammaS binding assay showed the down-regulation of the dopamine receptor function in the striatum in adult mice treated with DPAA. We also found that neonatal exposure to a low dose of DPAA induced motor learning impairment in mice. Furthermore, treatment with an extremely low dose of DPAA caused the activation of caspase-3, the increase in glial fibrillary acidic protein-like immunoreactivity (IR) and the reduction in levels of myelin-associated glycoprotein-IR in mouse cerebellum neuron/glia co-cultures. In addition, we found that neonatal exposure to a low dose of DPAA induced anxiogenic behavior in a plus maze in mice. Taken together, these results suggest that chronic treatment with DPAA may induce motor impairment in adult mice. Moreover, neonatal exposure to DPAA leads to the irreversible motor impairment associated with abnormalities in the cerebellum.

This study estimated the human health risk associated with ingesting inorganic arsenic through consumption of farmed oysters in Taiwan. Two hundred fifty-four samples of oyster (Crassostrea gigas) were collected from four townships in southwest coastal areas, where 90% of Taiwan's oysters are produced. The concentrations of total arsenic and arsenic species including As(V), As(III), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) were analyzed. The analytical results reveal that the ratio of mean concentration among the four townships of inorganic As to total concentration of As in oysters is approximately 1.64%. The mean concentrations of As(III) and As(V) in oysters from the four townships range from 0.071 to 0.145 microg/g, and 0.032 to 0.062 microg/g respectively. The estimated target cancer risks (TR), based on a 95% occurrence probability from ingesting inorganic As by consuming oysters at a rate of 18.6-56 g/day, range from 1.26 x 10(-5) to 3.82 x 10(-5). The probabilities of TR fell within the range 10(-6)-10(-4), suggesting that inorganic As uptake from farmed oysters is associated with a potential cancer risk. Moreover, a target hazard quotient (THQ) was used to evaluate the non-carcinogenic risk associated with ingesting inorganic As through oyster consumption at a rate of 18.6-56 g/day. The THQ values based on a 95% probability of exposure range from 0.071 to 0.214. All THQ values are below unity, indicating that farmed oyster consumption contributes only a little to the non-carcinogenic risk. Based on the estimation of the TR model, an ingestion rate of 1.6 g/day is recommended to meet the 95th percentile of carcinogenic risk, 10(-6), for exposure to inorganic As through the consumption of oysters in Taiwan.

The ill effects of human exposure to arsenic (As) have recently been reevaluated by government agencies around the world. This has lead to a lowering of As guidelines in drinking water, with Canada decreasing the maximum allowable level from 50 to 25 microg/L and the U.S. from 50 to 10 microg/L. Canada is currently contemplating a further decrease to 5 microg/L. The reason for these regulatory changes is the realization that As can cause deleterious effects at lower concentrations than was previously thought. There is a strong relationship between chronic ingestion of As and deleterious human health effects and here we provide an overview of some of the major effects documented in the scientific literature. As regulatory levels of As have been decreased, an increasing number of water supplies will now require removal of As before the water can be used for human consumption. While As exposure can occur from food, air and water, all major chronic As poisonings have stemmed from water and this is usually the predominant exposure route. Exposure to As leads to an accumulation of As in tissues such as skin, hair and nails, resulting in various clinical symptoms such as hyperpigmentation and keratosis. There is also an increased risk of skin, internal organ, and lung cancers. Cardiovascular disease and neuropathy have also been linked to As consumption. Verbal IQ and long term memory can also be affected, and As can suppress hormone regulation and hormone mediated gene transcription. Increases in fetal loss and premature delivery, and decreased birth weights of infants, can occur even at low (<10 microg/L) exposure levels. Malnourished people have been shown to be more predisposed to As-related skin lesions. A large percentage of the population (30-40%) that is using As-contaminated drinking water can have elevated As levels in urine, hair and nails, while showing no noticeable clinical symptoms, such as skin lesions. It is therefore important to carry out clinical tests of As exposure. Factors combining to increase/decrease the ill effects of As include duration and magnitude of As exposure, source of As exposure, nutrition, age and general health status. Analytical determinations of As poisoning can be made by examining As levels in urine, hair and toenails. Communities and individuals relying on groundwater sources for drinking water need to measure As levels to ensure that their supplies are safe. Communities with water As levels greater than 5 microg/L should consider a program to document As levels in the population.

The relationship of inorganic arsenic exposure through drinking water and total urinary arsenic excretion in a nonoccupationally exposed population was evaluated in a cross-sectional study in three mayor cities of Chile (Antofagasta, Santiago, and Temuco). A total of 756 individuals in three population strata (elderly, students, and workers) provided first morning void urine specimens the day after exposure and food surveys were administered. Arsenic intake from drinking water was estimated from analysis of tap water samples, plus 24-h dietary recall and food frequency questionnaires. Multilevel analysis was used to evaluate the effects of the age group and city factors adjusted by predictor variables. Arsenic levels in drinking water and urine were significantly higher in Antofagasta compared with the other cities. City-and individual-level factors, 12% and 88%, respectively, accounted for the variability in urinary arsenic concentration. The main predictors of urinary arsenic concentration were total arsenic consumption through water and age. These findings indicate that arsenic concentration in drinking water continues to be the principal contributing factor to exposure to inorganic arsenic in the Chilean population.

Atrazine is a herbicide used most frequently in North America, but it usually is encountered in mixtures of agrochemicals. Few atrazine exposure studies have been conducted using mixed pesticides; therefore, little data are available to suggest reliable means of discerning effects attributable to atrazine. The common freshwater macrophyte, Juncus effusus L., was exposed in 66 mesocosms to atrazine at two nominal concentrations (96 and 192 microg/L) with varying concentrations of chlorpyrifos, monosodium methanearsonate, and monomethylmercury. Exposure levels represented typical levels that might follow runoff or direct-spray application in enclosed waterbodies. Using shoot density and number of shoots shorter than 25 cm per unit area as response measurements, the growth effects of atrazine, even in varying pesticide mixes, could be detected as early as 16 d after initial exposure. Further growth effects specifically caused by atrazine also could be detected following a second exposure to the same toxicant mixture. Mesocosm tests offer greater control of natural variability than would be found in the natural environment and offer more realistic conditions than traditional laboratory/greenhouse studies. Therefore, in field testing, growth measurements should be accompanied by other confirmatory tests, such as pesticide concentrations in tissue and, possibly, chlorophyll concentrations, for measuring specific toxic effects of atrazine and other pesticides.

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.

2,4-dichlorophenoxyacetic acid and monosodium methanearsonate are often sold in commercial herbicide mixtures. Toxicity studies have been performed for each herbicide individually, but there is a dearth of information concerning the toxicity of these herbicides in a mixture. The following study examined the toxicity of a mixture of these two herbicides in the red swamp crawfish, Procambarus clarkii. 96-hour acute toxicity assays were performed to determine whether surfactant significantly altered the toxicity of these herbicides individually or in combination. Markings additive index was calculated to identify the interactions of the herbicide mixture. Surfactant was observed to significantly increase the toxicity of 2,4-dichlorophenoxyacetic acid and the toxicity of the herbicide mixture. The herbicide mixture alone displayed half the toxicity of the individual herbicides, but the mixture with surfactant was twice as toxic as the individual herbicides. The synergistic action of surfactant may be attributed to increased pesticide absorption across biological membranes. 2,4-dichlorophenoxyacetic acid and surfactant may also compromise gill function, increasing the sensitivity of the crawfish to herbicide toxicity. The antagonistic effects of the herbicide mixture in the absence of surfactant may be caused by competition of both herbicides for the same sites of activity.

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process.

The spatial distribution of chronic arsenicosis due to consumption of arsenic contaminated tube well water in different districts of West Bengal was gradually unfolding since 1983. Arsenical dermatosis was found to be the commonest and earliest manifestation of chronic arsenic toxicity. This study was conduct in Baruipur block of South 24 Parganas district of West Bengal. Total 313 people selected from three randomly selected villages with reported arsenic contamination in tube well water and 342 people living three randomly selected villages without such evidence of contamination were examined as control population. 5.97% of exposed population and 2.05% of unexposed population showed melanosis (p < 0.01). Moreover, 5.11% of exposed population and 0.88% of unexposed population showed keratosis (p < 0.01). The prevalence of dermatosis among exposed population was also seen to have increased with increasing age, from 7.19% in 0-19 year age group to 37.50% in above 40 year group (p < 0.001). Prevalence was also found to be more with increase in level of contamination. The prevalence rate of dermatosis among unexposedgroup was 2.92%. But age adjusted prevalence rate among exposed group was 19.08% at arsenic contamination level of 0.487 ppm. Mean arsenic concentration in nail and hair samples of exposed group was also found higher than the prescribed limit.

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.

To elucidate the associations of arsenic-induced skin cancer with serum beta-carotene level and arsenic methylation capability, a total of 654 residents of age 30 or older were recruited from three arseniasis-hyperendemic villages in Taiwan and regularly examined for skin lesions during the follow-up period. There were 33 cases affected with newly diagnosed skin cancer during the follow-up, giving an incidence of 14.74 per 1000 person-years. Although most study subjects had stopped consuming high-arsenic artesian well water more than 20 years ago, the risk of skin cancer was found to increase significantly with cumulative arsenic exposure before the cessation of drinking artesian well water in a dose-response relationship. Frozen serum samples collected at the recruitment from newly developed skin cancer cases and matched controls were tested for beta-carotene levels by high-performance liquid chromatography. Frozen urine samples of these subjects were examined by high-performance liquid chromatography to speciate arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), and dimethylarsinic acid and then quantitated by hydride generator combined with atomic absorption spectrometry. Skin cancer cases had a significantly lower serum level of beta-carotene than matched healthy controls. Although the primary methylation capability indexed by the ratio of MMA/(AsIII + AsV) was greater in cases than in controls, the secondary methylation capability indexed by the ratio of dimethylarsinic acid/MMA was lower in cases than in controls. An elevated proportion of MMA in total urinary arsenic level was associated with an increased risk of skin cancer. Subjects with a cumulative arsenic exposure of > or = 20.0 mg/liter-year and a proportion of MMA in total urinary arsenic level >26.7% had a multivariate-adjusted odds ratio of developing skin cancer as high as 20.91 (95% confidence interval, 2.63-166.5) compared wih those who had a cumulative arsenic exposure of <20.0 mg/liter-year and a MMA percentage of < or = 26.7%. Whether the association with capability of inorganic methylation is also applied to cancers of internal organs, including lung, liver, and urinary bladder, remains to be elucidated.

The exfoliated cell micronucleus (MN) assay using fluorescent in situ hybridization (FISH) with a centromeric probe is a rapid method for determining the mechanism of MN formation in epithelial tissues exposed to carcinogenic agents. Here, we describe the use of this assay to detect the presence or absence of centromeric DNA in MN induced in vivo by radiation therapy and chronic arsenic (As) ingestion. We examined the buccal cells of an individual receiving 6,500 rads of photon radiation to the head and neck. Exfoliated cells were collected before, during, and after treatment. After radiation exposure a 16.6-fold increase in buccal cell MN frequency was seen. All induced MN were centromere negative (MN-) resulting from chromosome breakage. This finding is consistent with the clastogenic action of radiation and confirmed the reliability of the method. Three weeks post-therapy, MN frequencies returned to baseline. We also applied the assay to exfoliated bladder cells of 18 people chronically exposed to high levels of inorganic arsenic (In-As) in drinking water (average level, 1,312 micrograms As/L) and 18 matched controls (average level, 16 micrograms As/L). The combined increase in MN frequency was 1.8-fold (P = 0.001, Fisher's exact test). Frequencies of micronuclei containing acentric fragments (MN-) and those containing whole chromosomes (MN+) both increased (1.65-fold, P = 0.07, and 1.37-fold, P = 0.15, respectively), suggesting that arsenic may have both clastogenic and weak aneuploidogenic properties in vivo. After stratification on sex, the effect was stronger in male than in female bladder cells. In males the MN- frequency increased 2.06-fold (P = 0.07) while the frequency of MN+ increased 1.86-fold (P = 0.08). In addition, the frequencies of MN- and MN+ were positively associated with urinary arsenic and its metabolites. However, the association was stronger for micronuclei containing acentric fragments. By using FISH with centromeric probes, the mechanism of chemically induced genotoxicity can now be determined in epithelial tissues.