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Risk assessment of a former military base contaminated with organoarsenic-based warfare agents: uptake of arsenic by terrestrial plants.

Organoarsenic-based chemical warfare agents (CWAs) such as the sternutators diphenylchloroarsine (CLARK I), diphenylcyanoarsine (CLARK II) or phenyldichloroarsine (PFIFFIKUS) still pose a notable risk in countries where former military bases that have stored these weapons have not yet been reclaimed. In fact, this is the case for many countries of Eastern Europe and the CIS. One of the most important military bases of the former Third Reich, the Heeresmunitionsanstalt I and II, is situated close to the German-Polish border at Loecknitz (Fig. 1). The German army stored and decanted different compounds of CWAs at this military base until 1945. When the Soviet Army destroyed the base in 1946, large amounts of CWAs and other organoarsenic compounds polluted the soil. Today up to 250 g (!) of arsenic may be found in 1 kg of soil at some places in this area. Since 1991, a Government Working Group has been working on the risk assessment in order to define the scope of reclamation measures. This study investigates the contamination and the uptake of arsenic by plants because little is known about the bioavailability and metabolism of sternutators and their constituents. The total arsenic concentration of nine different species of terrestrial plants with at least six samples per species is presented. In spite of the considerable arsenic contamination of the soil (mean value 923 mg arsenic/kg soil) the plant contamination remained comparably low. The median value of arsenic contamination of the above-ground organs of velvet grass, Holcus lanatus, was 0.7 mg/kg dry wt. and the mean value was 4.3 mg/kg dry wt. due to some highly contaminated samples. The highest arsenic concentration registered was 26 mg/kg dry wt. in a sample of H. lanatus, which was most probably caused by soil particles adhering to the plant. The chemical structure of the arsenic compounds carried by the above-ground plant organs has been determined by gas chromatographic investigations and showed an uptake of triphenyl arsine by the plants.

Arsenic↗

Arsenic trioxide sensitivity is associated with low level of glutathione in cancer cells.

Arsenic trioxide (As2O3) is a novel anticancer agent, which has been found to induce remission in acute promyelocytic leukaemic patients following daily intravenous administration. The therapeutic value of As2O3 in other cancers is still largely unknown. Cytotoxic tests in a panel of cancer cell lines showed that bladder cancer, acute promyelocytic leukaemic and gastrointestinal cancer cells were the most sensitive to As2O3 among 17 cell lines tested. Cellular glutathione (GSH) system plays an important role in arsenic detoxification in mammalian cells. Cancer cells that were intrinsically sensitive to As2O3 contained lower levels of GSH, whereas resistant cancer cells contained higher levels of GSH. On the other hand, there was no association of glutathione-S-transferase-pi or multidrug resistance-associated protein 1 levels with arsenic sensitivity in these cancer cells. Multidrug-resistant cancer cells that were cross-resistant to arsenic contained higher levels of GSH or multidrug-resistance-associated protein 1 than their drug-sensitive parental cells. Cancer cells become more sensitive to arsenic after depletion of cellular GSH with L-buthionine sulphoximine. We concluded that cellular GSH level is the most important determinant of arsenic sensitivity in cancer cells. Cellular GSH level and its modulation by buthionine sulphoximine should be considered in designing clinical trials using arsenic in solid tumours.

Antimetabolites, Antineoplastic↗

Neurologic evaluation of a population exposed to arsenic in Alaskan well water.

One hundred forty-seven persons exposed to arsenic from well water were evaluated by neurologic examination and nerve conduction studies. Total arsenic concentrations in well water ranged from 1 to 4781 micrograms/L and from 6 to 4964 micrograms/L in urine; a calculated index of arsenic ingestion ranged from 1 to 4521 micrograms/day. No dose-response relationship existed between arsenic ingestion and symptoms or physical findings compatible with peripheral neuropathy. Five of six persons with symptoms or physical findings suggestive of sensory neuropathy had normal nerve conduction velocities. Thirteen persons with elevated arsenic ingestion but no signs or symptoms of neuropathy had one or more abnormal nerve conduction velocities. No dose-response relationship, however, existed between arsenic ingestion and nerve conduction velocities. The authors concluded that arsenic ingestion from well water at the concentrations found in this Alaskan community did not result in clinical or subclinical neuropathy.

Adult↗

Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two compounds.

Arsenic trioxide (As2O3) induces remission in patients with acute promyelocytic leukemia (APL). To better understand molecular mechanisms of arsenic actions, this study investigated the effect of two different arsenic compounds on gene expression of apoptosis and cellular proliferation related genes. The Wilms' tumor gene (wt1) is up-regulated in acute myeloid leukemia (AML) and a variety of leukemia cell lines. The expression of wt1 in these cells is proposed to have an anti-apoptotic effect. HL-60 and K562 were treated with arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) at concentrations between 0 - 10 microM for up to 48 h. The induction of apoptosis was accompanied by down-regulation of hTERT and wt1 mRNA and protein expression but up-regulation of par-4. Low concentrations of 0.1 microM arsenic induced expression of the anti-apoptotic bcl-2 gene in both cell lines HL-60 and K562. There were no major differences encountered between compounds. After arsenic treatment of the leukemia cell lines HL-60 and K562 the up-regulation of par-4 may contribute to the induction of apoptosis rather than down-regulation of bcl-2. The therapeutic effect of arsenic is the induction of apoptosis by modulating the gene expression profile of pro- and anti-apoptotic genes including the wt1 gene.

Apoptosis↗

Effect of a chemical mixture on dermal penetration of arsenic and nickel in male pig in vitro.

The effect of a chemical mixture on the dermal penetration of arsenic or nickel was assessed by applying arsenic-73 or nickel-63 alone or with the chemical mixture to dermatomed male pig skin samples in flow-through diffusion cells. The chemical mixture consisted of chloroform, phenanthrene, and toluene for arsenic penetration studies and phenol, toluene, and trichloroethylene (TCE) for nickel studies. These are predominant chemicals found at hazardous waste sites. Arsenic and nickel bind to skin after dermal exposure. Total penetration of arsenic and nickel in the chemical mixture were significantly increased by 33% and 20% compared to arsenic and nickel alone, respectively. While more radioactivity penetrated skin with chemical treatment than metal alone, significantly less radioactivity was loosely adsorbed to skin and could be easily washed off from the skin surface with soap and water. The results of this study indicate that the potential health risk from dermal exposure to arsenic or nickel is enhanced if other chemicals are present.

Animals↗

Laboratory case identification of arsenic in Ronpibul village, Thailand (2000-2002).

Ronpibul village dwellers in the southern part of Thailand have been exposed to arsenic in the water and the environment over three generations. Over the past decades, clean water supplies, utilization and consumption have been introduced to the area. The villagers still use and select rainwater to other forms of potable water. In 2000, the epidemiological survey by Siripitayakunkit (Siripitayakunkit, U. Survey of Chronic Arsenic Poisoning in Ronpiboon, Nakhon Si Thammarat, Thailand, 2000. Proc. 6th International Conference on the Biochemistry of Trace Elements, Guelph, Canada) showed prevalence rate at 24.7%, by using the skin lesion as selection criteria. In 2000-2002, attempt to initiate the local arsenic patient center, we investigated the population at risk in three villages. The laboratory analyses cover urine arsenic level, urine sugar screening and skin lesion classified by dermatologist. The result showed the prevalence of 5.99% of melanosis and 8.67% of hyperkeratosis, 3.84% of urine sugar > 100 mg/dL and 6.33% urine arsenic > 50 microg/g creatinine. There were low to negligible correlation between arsenic urine with urine sugar (r2 = 0.241) and arsenic urine with skin lesion (r2 = 0.058).

Arsenic↗

Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy.

INTRODUCTION: Arsenic trioxide is effective and approved for treatment of relapsed or refractory acute promyelocytic leukemia (APL) cases resistant to all-trans retinoic acid (ATRA), but its effect on new cases of APL is not clear. MATERIALS AND METHODS: We studied 111 patients with APL. Arsenic trioxide was infused at 0.15 mg/kg daily dose, until complete remission was achieved. Then, after 28 days of rest, arsenic trioxide was infused daily for 28 days as consolidation therapy. We studied minimal residual disease (MRD) by semi-sensitive reverse transcription polymerase chain reaction (RT-PCR) on peripheral blood samples. RESULTS: Complete remission was observed in 95 patients (85.6%). With the median (range) follow-up period of 16.5 (1-57) months, 1- and 2-year disease-free survival was 88.3% and 63.7%, respectively; 24 patients relapsed, 19 of whom achieved a second complete remission, again by arsenic trioxide. Third and fourth remissions were seen in some relapsed patients, again by arsenic trioxide. For patients in complete remission, 1- and 3-year survival was 95.5% and 87.6%, respectively. MRD was positive in four (8.3%) out of 48 cases during 1 year after remission induction; three of them relapsed clinically. CONCLUSIONS: Arsenic trioxide is effective as first-line treatment for APL. Results of arsenic trioxide combination therapy with chemotherapy/ATRA requires further study.

Adolescent↗

Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic.

Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL-2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM-CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL-4, IL-10, or IFN-gamma by PHA-activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM-CSF secretion that may be associated with chronic inflammation.

Arsenic↗

Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies.

PURPOSE OF REVIEW: While arsenic has long been known as a poison and environmental carcinogen, its dramatic effect in the treatment of acute promyelocytic leukemia (APL) has made its mechanism of action a topic of intense interest. This paper reviews recent findings that reveal why a traditional poison has become a magical potion for a major type of APL, which is characterized by a balanced chromosomal translocation t(15;17). RECENT FINDINGS: Daily IV infusion of arsenic trioxide (As2O3; ATO) for 30 to 40 days can lead to complete remission in about 85% of patients with newly diagnosed or relapsed APL. Oral preparations of ATO and tetra-arsenic tetra-sulfide (As4S4) seem to be as effective as parenteral ATO, with similar toxicity profiles. The combination of all-trans retinoic acid and ATO in patients with newly diagnosed APL has yielded more durable remission than monotherapy. The mechanism of arsenic cytotoxicity is thought to involve posttranslational modification followed by degradation of the PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein; targeting of PML to nuclear bodies with restoration of its physiologic functions; and production of reactive oxygen species (ROS) by NADPH oxidase in leukemic cells or collapse of the mitochondrial transmembrane potential. The understanding of arsenic cytotoxicity has stimulated modifications that promise to improve efficacy, such as interfering with ROS scavenging or boosting of ROS production to enhance the cytotoxicity, and adding cAMP or interferons to ATO regimens. SUMMARY: Recent advances in the clinical use of arsenic, the mechanism of arsenic-mediated cytotoxicity, and modulations of ATO to increase its efficacy and expand its clinical spectrum are reviewed.

Antineoplastic Agents↗

A pilot study on the urinary excretion of porphyrins in human populations chronically exposed to arsenic in Mexico.

1 The aim of this pilot study was to investigate if the porphyrinuria produced by arsenic in rodents was present in humans chronically exposed to arsenic via drinking water. 2 The concentrations of uroporphyrin, coproporphyrin and total arsenic in urine were compared between 21 individuals exposed to arsenic in their drinking water (0.390 mg l-1) and 19 controls exposed to 0.012 mg l-1. 3 Arsenic-exposed individuals had significantly higher total arsenic concentrations in their urine than the control group. No increase in urinary porphyrin excretion was found in exposed individuals. However, an inversion of the coproporphyrin/uroporphyrin (COPRO/URO) ratio was observed in most exposed individuals. This inversion was caused both, by a decrease in coproporphyrin excretion and an increase in uroporphyrin excretion. 4 No demonstrable correlations between porphyrin excretion, the COPRO/URO ratio and total arsenic concentration in urine were found in exposed individuals.

Adult↗

Influence of thyroxine and n-propylthiouracil on nephro-toxicity of inorganic arsenic in rat.

The effect of hyper or hypoactive thyroid on the renal toxicity of arsenic trioxide has been studied in rats. It was observed that pre-treatment of rats with thyroxine stimulates arsenic excretion in urine. The anti-thyroid drug n-propylthiouracil (PTU), inhibits the accumulation of arsenic in renal tissue. Both treatments affect the renal pathology. Histopathological lesions are less severe in PTU and arsenic-treated rats in comparison to thyroxine and arsenic-treated rats. Ultrastructural studies support light microscopical observations. An adaptive response was noticed against arsenic in PTU pre-treated rats. We attribute this response to decreased glutathione-S-transferase (GSH) activity and increased GSH synthesis in the kidney. A relationship between thyroidal activity and arsenic toxicity is suggested by present observations.

Animals↗

Intracellular calcium disturbances induced by arsenic and its methylated derivatives in relation to genomic damage and apoptosis induction.

Arsenic and its methylated derivatives are contaminants of air, water, and food and are known as toxicants and carcinogens. Arsenic compounds are also being used as cancer chemotherapeutic agents. In humans, inorganic arsenic is metabolically methylated to mono-, di-, and trimethylated forms. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In recent years, the correlation between arsenic exposure, cytotoxicity and genotoxicity, mutagenicity, and tumor promotion has been established, as well as the association of arsenic exposure with perturbation of physiologic processes, generation of reactive oxygen species, DNA damage, and apoptosis induction. Trivalent forms of arsenic have been found to induce apoptosis in several cellular systems with involvement of membrane-bound cell death receptors, activation of caspases, release of calcium stores, and changes of the intracellular glutathione level. It is well known that calcium ion deregulation plays a critical role in apoptotic cell death. A calcium increase in the nuclei might lead to toxic effects in the cell. In this review, we highlight the relationship between induced disturbances of calcium homeostasis, genomic damage, and apoptotic cell death caused by arsenic and its organic derivatives.

Animals↗

Occurrence and transformation of arsenic in the marine environment.

Among the trace elements, arsenic appears to possess a unique position in the environment. When comparing terrestrial and marine organisms there seems to be a significant difference between both level and chemical forms of arsenic. The level of arsenic in terrestrial organisms is seldom above 1 ppm (dry material) whereas the corresponding values for marine organisms vary from several parts per million up to more than 100 ppm. Furthermore, results so far show that marine organisms are able to convert inorganic arsenic into organic arsenic compounds. No evidence points to a corresponding ability in the terrestrial ones. In the aquatic organisms the arsenic is present as both lipid soluble and water soluble compounds. The water-soluble organic arsenic compounds have a basic character and are very stable to chemical and metabolic breakdown.

Animals↗

Test of environmental exposure to arsenic and hearing changes in exposed children.

Arsenic determination was carried out on hair, urine, and blood samples taken from groups of 10-year-old boys, each numbering 20 to 25 individuals, residing in a region polluted by arsenic. In all the examined materials considerably elevated concentrations of arsenic were found. The relation of the observed levels of arsenic to the distance of the place of residence up to a distance of more than 30 km from the source of the emissions was studied. On the basis of the results obtained, the most advantageous material for estimation of nonoccupational exposure to arsenic seems to be hair, in spite of some problems with the decontamination procedure involved. Considerable variability among individual arsenic values in the hair makes group examination a necessity. Hearing changes were analyzed in a group of 56 10-year old children residing near a power plant burning local coal of high arsenic content. The results of both audiometric and clinical examination were compared with those of control group numbering 51 children of the same age living outside the polluted area. The highly standardized audiometric and clinical examination were completed with a questionnaire analysis concerning the personal medical histories of the children. The obtained data were elaborated statistically by means of the chi(2)- test. In the case of air conduction, important hearing losses were found at frequencies of 125, 250 and 8000 Hz, especially at the lowest frequency range. Significant degrees of hearing loss were found in bone conduction as well as in the corresponding ranges of frequencies. The high statistical significance of the hearing impairments found points to very low probability of their being only an "accidental" finding. The possibility of toxic damage to the ear cannot yet be excluded.

Arsenic↗

The relationship of arsenic levels in drinking water and the prevalence rate of skin lesions in Bangladesh.

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

Adult↗

Resistance to oxidative stress in a freshwater fish Channa punctatus after exposure to inorganic arsenic.

The biochemical toxicity of arsenic trioxide (AsIII) in a freshwater edible fish Channa punctatus has been studied on exposures ranging from 7 to 90 d. The arsenic concentration increased exponentially in liver, kidney, gills, and muscles of fish up to 60 d of exposure to arsenic. However, arsenic concentration in these tissues declined at 90 d of exposure. This relationship between period of exposure and concentration of arsenic in selected tissues suggests an adaptive response of fish to arsenic. Furthermore, exposure to arsenic-induced lipid peroxidation in these organs increased initially at 7 d of exposure; however, it decreased up to 60 d of exposure but increased again at 90 d of treatment. Values of reduced glutathione (GSH) reflected the observations of lipid peroxidation. The role of GSH in this adaptive response has been discussed.

Animals↗

Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells.

In recent years, breast cancers have aroused much concern. Together with a growing incidence all over the world, the development of drug resistance to tamoxifen, the most commonly prescribed chemotherapeutic drug for breast cancer patients, has highlighted the importance of developing a new chemotherapeutic drug in combating breast cancer. With the aim of treating breast cancers, the anti-tumor effects of arsenic trioxide in MCF-7 cells have been studied. MCF-7 cells are estrogen responsive cells which mimic breast cancers at the early stage. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and direct cell counting were used to measure cell proliferation. The mechanisms of action were elucidated through the measurement of estrogen receptor (ER) binding, mRNA and protein levels of ERalpha and its activity. We have demonstrated that arsenic trioxide was capable of reducing cell survival in MCF-7 cells via the suppression of the estrogen-induced growth stimulatory effects in MCF-7 cells. Arsenic trioxide was shown to suppress the action of estrogen through the regulation of the ERalpha signaling pathway. Arsenic trioxide could down-regulate ERalpha mRNA and protein levels without competing with estrogen for ERalpha binding. Arsenic trioxide also inhibited the transcription activity mediated by the ERalpha signaling pathway and ultimately it down-regulated c-myc protein expression and inhibited cell entry to S phase under estrogen's stimulation. In conclusion, arsenic trioxide could inhibit the growth of MCF-7 cells by reducing the growth stimulatory effect of estrogen. As estrogen is a primary risk factor in promoting the growth of breast tumor cells, the anti-estrogenicity exhibited by arsenic trioxide sheds light on the therapy of breast cancer.

Arsenic Trioxide↗

Determination of arsenic species in marine samples by HPLC-ICP-MS.

Arsenic speciation analysis in marine samples was performed using high performance liquid chromatography (HPLC) with ICP-MS detection. The separation of eight arsenic species viz. arsenite (As(III)), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), arsenate (As(V)), arsenobetaine, trimethylarsine oxide (TMAO), arsenocholine and tetramethylarsonium ion (TeMAs) was achieved on a Shiseido Capcell Pak C18 column by using an isocratic eluent (pH 3.0), in which condition As(III) and MMA were co-eluted. The entire separation was accomplished in 15 min. The detection limits for 8 arsenic species by HPLC/ICP-MS were in the range of 0.02 - 0.10 microg L(-1) based on 3sigma of blank response (n=9). The precision was calculated to be 3.1-7.3% (RSD) for all eight species. The method then successfully applied to several marine samples e.g., oyster, scallop, fish, and shrimps. For the extraction of arsenic species from seafood products, the low power microwave digestion was employed. The extraction efficiency was in the range of 52.9 - 112.3%. Total arsenic concentrations were analyzed by using the microwave acid digestion. The total arsenics in the certified reference materials (DORM-2 and TORT-2) were analyzed and agreed with the certified values. The concentrations of arsenics in marine samples were in the range 6.6 - 35.1 microg g(-1).

Animals↗