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arsenic articles

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  • deborahbarrie@hotmail.com
    Hi Everybody, Here is a rather long list of recent articles on arsenic. I would like to thank Dr Sara Bennett for them. These articles speak very clearly that
    Message 1 of 2 , Aug 31, 2004
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      Hi Everybody,
      Here is a rather long list of recent articles on arsenic. I would like to thank Dr Sara Bennett for them. These articles speak very clearly that arsenic and it�s effects on the body are just really beginning to be understood and that this is most certainly a toxin we do not need in our everyday environment. The continued stand of the government not to remove arsenic treated wood from playgrounds and homes speaks more to their inability to not know what to do than their position of not finding it a health risk.
      Take care everybody and please keep safe.

      Animal models for arsenic carcinogenesis: inorganic arsenic is a
      transplacental carcinogen in mice. MP Waalkes, J Liu, JM Ward, and
      BA Diwan. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 377.

      Abstract: Inorganic arsenic is a known human carcinogen causing
      tumors of the skin, urinary bladder, lung, liver, kidney, and
      possibly other organs. However, the animal models for inorganic
      arsenic carcinogenesis have been limited and development has been
      problematic. Gestation is often a period of high sensitivity to
      carcinogenesis so we investigated inorganic arsenite as a
      transplacental carcinogen in mice. Pregnant C3H mice were exposed to
      sodium arsenite (0, 42.5, and 85 ppm as arsenic) in the drinking
      water for a brief period during gestation (from gestation day 8 to
      18), with no further arsenic exposure or other treatments. The
      offsprings were monitored up to 90 weeks. Transplacental inorganic
      arsenic exposure produced a dose-dependent induction of tumors in
      the liver, adrenal, lung, and ovary in the offsprings after they had
      reached adulthood. This included hepatocellular carcinoma (HCC), a
      tumor associated with arsenic exposure in humans. These tumors
      occurred when mice became adults in the absence of any other
      treatments and well after arsenic exposure had ended. Genomic
      analysis of liver tumors and tumor-surrounding tissues revealed
      several patterns of aberrant gene expression associated with
      transplacental arsenic carcinogenesis. This animal model
      demonstrated that inorganic arsenic could act as a "complete"
      transplacental carcinogen in mice. In addition, other important
      animal models for inorganic arsenic as a skin tumor co-promoter or
      as a co-carcinogen are discussed. The development of these animal
      models should advance our understanding of the mechanisms of
      inorganic arsenic carcinogenesis.


      Evaluation of DNA damage in patients with arsenic poisoning: urinary
      8-hydroxydeoxyguanine. H Yamauchi, Y Aminaka, K Yoshida, G Sun, J
      Pi, and MP Waalkes. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p.

      Abstract: The relationship between arsenic exposure and DNA damage
      in patients with acute or chronic arsenic poisoning was analyzed.
      Urinary 8-hydroxydeoxyguanine (8-OHdG) concentrations were measured
      as an indication of oxidative DNA damage. A remarkable increase in 8-
      OHdG in the urine was observed in 60% of 52 patients with acute
      arsenic poisoning from the accidental oral intake of the arsenic
      trioxide. This was two- to threefold higher than levels in normal
      healthy subjects (n = 248). There was a clear relationship between
      arsenic concentrations in urine after acute poisoning and elevated
      levels of 8-OHdG. Levels of urinary 8-OHdG returned to normal within
      180 days after the acute arsenic poisoning event. In patients
      chronically poisoned by the consumption of well water with elevated
      levels of arsenate [As(V)], elevated 8-OHdG concentrations in urine
      were also observed. A significant correlation between the 8-OHdG
      levels and arsenic levels in the urine was observed in 82 patients
      with chronic poisoning. Thus, evidence of oxidative DNA damage
      occurred in acute arsenic poisoning by arsenite [As(III)] and in
      chronic arsenic poisoning by As(V). In chronic poisoning patients
      provided low-arsenic drinking water, evidence of DNA damage subsided
      between 9 months and 1 year after the high levels of arsenic intake
      were reduced. The initial level of arsenic exposure appeared to
      dictate the length of this recovery period. These data indicate that
      some aspects of chronic and acute arsenic poisoning may be
      reversible with the cessation of exposure. This knowledge may
      contribute to our understanding of the risk elevation from arsenic
      carcinogenesis and perhaps be used in a prospective fashion to
      assess individual risk.


      Inhibition of insulin-dependent glucose uptake by trivalent
      arsenicals: possible mechanism of arsenic-induced diabetes. FS
      Walton, AW Harmon, DS Paul, Z Drobna, YM Patel, and M Styblo.
      Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 424.

      Abstract: Chronic exposures to inorganic arsenic (iAs) have been
      associated with increased incidence of noninsulin (type-2)-dependent
      diabetes mellitus. Although mechanisms by which iAs induces diabetes
      have not been identified, the clinical symptoms of the disease
      indicate that iAs or its metabolites interfere with insulin-
      stimulated signal transduction pathway or with critical steps in
      glucose metabolism. We have examined effects of iAs and methylated
      arsenicals that contain trivalent or pentavalent arsenic on glucose
      uptake by 3T3-L1 adipocytes. Treatment with inorganic and methylated
      pentavalent arsenicals (up to 1 mM) had little or no effect on
      either basal or insulin-stimulated glucose uptake. In contrast,
      trivalent arsenicals, arsenite (iAs(III)), methylarsine oxide (MAs
      (III)O), and iododimethylarsine (DMAs(III)O) inhibited insulin-
      stimulated glucose uptake in a concentration-dependent manner.
      Subtoxic concentrations of iAs(III) (20 microM), MAs(III)O (1
      microM), or DMAs(III)I (2 microM) decreased insulin-stimulated
      glucose uptake by 35-45%. Basal glucose uptake was significantly
      inhibited only by cytotoxic concentrations of iAs(III) or MAs(III)O.
      Examination of the components of the insulin-stimulated signal
      transduction pathway showed that all trivalent arsenicals suppressed
      expression and possibly phosphorylation of protein kinase B
      (PKB/Akt). The concentration of an insulin-responsive glucose
      transporter (GLUT4) was significantly lower in the membrane region
      of 3T3-L1 adipocytes treated with trivalent arsenicals as compared
      with untreated cells. These results suggest that trivalent
      arsenicals inhibit insulin-stimulated glucose uptake by interfering
      with the PKB/Akt-dependent mobilization of GLUT4 transporters in
      adipocytes. This mechanism may be, in part, responsible for the
      development of type-2 diabetes in individuals chronically exposed to


      The accumulation and toxicity of methylated arsenicals in
      endothelial cells: important roles of thiol compounds. S Hirano, Y
      Kobayashi, X Cui, S Kanno, T Hayakawa, and A Shraim. Toxicol Appl
      Pharmacol 1 Aug 2004 198(3): p. 458.

      Abstract: Excess intake of arsenic is known to cause vascular
      diseases as well as skin lesions and cancer in humans. Recent
      reports suggest that trivalent methylated arsenicals, which are
      intermediate metabolites in the methylation process of inorganic
      arsenic, are responsible for the toxicity and carcinogenicity of
      environmental arsenic. We investigated acute toxicity and
      accumulation of monomethylarsonic acid (MMA(V)), dimethylarsinic
      acid (DMA(V)), trimethylarsine oxide (TMAO), and monomethylarsonous
      acid diglutathione (MMA(III) (GS)(2)) in rat heart microvessel
      endothelial (RHMVE) cells. MMA(V) (LC(50) = 36.6 mM) and DMA(V) (LC
      (50) = 2.54 mM) were less toxic than inorganic arsenicals (cf. LC
      (50) values for inorganic arsenite (iAs(III)), and inorganic
      arsenate (iAs(V)) was reported to be 36 and 220 microM,
      respectively, in RHMVE cells. TMAO was essentially not toxic.
      However, MMA(III) (GS)(2) was highly toxic (LC(50) = 4.1 microM).
      The order of cellular arsenic accumulation of those four organic
      arsenic compounds was MMA(III) (GS)(2) >> MMA(V) > DMA(V) > TMAO. MMA
      (III) (GS)(2) was efficiently taken up by the cells and cellular
      arsenic content increased with the concentration of MMA(III) (GS)(2)
      in culture medium. N-acetyl-l-cysteine (NAC) reduced cellular
      arsenic content in DMA(V)-exposed cells and also decreased the
      cytotoxicity of DMA(V), whereas it changed neither cellular arsenic
      content nor the viability in MMA(V)-exposed cells. mRNA levels of
      heme oxygenase-1 (HO-1) were decreased by NAC in DMA(V)-exposed, but
      MMA(V)-exposed cells. Buthionine sulfoximine (BSO), a cellular
      glutathione (GSH) depleting agent, enhanced the cytotoxicity of MMA
      (V). However, BSO reduced, rather than enhanced, the cytotoxicity of
      DMA(V). These results suggest that intracellular GSH modulated the
      toxic effects of arsenic in opposite ways for MMA(V) and DMA(V).
      Even though intracellular GSH decreased the cytotoxicity of MMA(V),
      extracellularly added GSH enhanced the cytotoxicity of MMA(V). The
      use of high-performance liquid chromatography (HPLC)-inductively
      coupled plasma mass spectrometric analyses suggested that a small
      amount of MMA(V) was converted to MMA(III) (GS)(2) in the presence
      of GSH. These results suggest that MMA(III) (GS)(2) is highly toxic
      compared to other arsenic compounds because of faster accumulation
      of this species by cells, in addition to having the toxic nature of
      methylated trivalent organic arsenics.


      Arsenic contamination awareness among the rural residents in
      Bangladesh. BK Paul. Soc Sci Med 1 Oct 2004 59(8): p. 1741.

      Abstract: Arsenic poisoning of tubewell water, which constitutes
      the primary source of drinking water, has become the greatest health
      threat to the people of rural Bangladesh. Somewhere between 35 to 57
      million people in the country are now suspected of being affected by
      drinking water contaminated with arsenic. While the Bangladesh
      government, non-government organizations (NGOs), and bilateral and
      multilateral assistance agencies are involved in combating this
      dreadful problem, all of their efforts to date have proceeded
      without having grassroots information about arsenic poisoning. The
      objectives of this study are to investigate the level of knowledge
      rural residents have regarding arsenic poisoning and to identify the
      correlates of that knowledge. Questionnaire surveys administered
      among residents of four rural areas in Bangladesh provided the major
      data source for this study. Twenty villages were selected from
      moderate and low arsenic risk regions and a total of 356
      respondents, 177 from medium risk regions and 179 from low risk
      regions, were interviewed. Analysis of the survey data reveals that
      arsenic awareness is currently not widespread in the study villages,
      particularly in the low arsenic risk region. There are also gaps in
      arsenic knowledge regarding the diseases caused by arsenic poisoning
      and mitigating measures available to prevent contamination. This
      study identified arsenic risk region, level of education, gender,
      and age as important determinants of arsenic knowledge. The findings
      of this study will aid in making existing health education programs
      more effective and in reducing the risk of developing arsenic-
      related illnesses.


      The effect of arsenic mitigation interventions on disease burden in
      Bangladesh. KM Lokuge, W Smith, B Caldwell, K Dear, and AH Milton.
      Environ Health Perspect 1 Aug 2004 112(11): p. 1172.

      Abstract: Many interventions have been advocated to mitigate the
      impact of arsenic contamination of drinking water in Bangladesh.
      However, there are few data on the true magnitude of arsenic-related
      disease in Bangladesh nationally. There has also been little
      consideration given to possible adverse effects of such
      interventions, in particular, diarrheal disease. The purpose of this
      study was to estimate and compare the likely impacts of arsenic
      mitigation interventions on both arsenic-related disease and water-
      borne infectious disease. We found that arsenic-related disease
      currently results in 9,136 deaths per year and 174,174 disability-
      adjusted life years (DALYs; undiscounted) lost per year in those
      exposed to arsenic concentrations > 50 microg/L. This constitutes
      0.3% of the total disease burden in Bangladesh in terms of
      undiscounted DALYs. We found intervention to be of overall benefit
      in reducing disease burden in most scenarios examined, but the
      concomitant increase in water-related infectious disease
      significantly reduced the potential benefits gained from
      intervention. A minimum reduction in arsenic-related DALYs of 77%
      was necessary before intervention achieved any reduction in net
      disease burden. This is assuming that interventions were provided to
      those exposed to > 50 microg/L and would concomitantly result in a
      20% increase in water-related infectious disease in those without
      access to adequate sanitation. Intervention appears to be justified
      for those populations exposed to high levels of arsenic, but it must
      be based on exposure levels and on the effectiveness of
      interventions not only in reducing arsenic but in minimizing risk of
      water-related infections.


      Elucidating the pathway for arsenic methylation. DJ Thomas, SB
      Waters, and M Styblo. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p.

      Abstract: Although biomethylation of arsenic has been studied for
      more than a century, unequivocal demonstration of the methylation of
      inorganic arsenic by humans occurred only about 30 years ago.
      Because methylation of inorganic arsenic activates it to more
      reactive and toxic forms, elucidating the pathway for the
      methylation of this metalloid is a topic of considerable importance.
      Understanding arsenic metabolism is of public health concern as
      millions of people chronically consume drinking water that contains
      high concentrations of inorganic arsenic. Hence, the focus of our
      research has been to elucidate the molecular basis of the steps in
      the pathway that leads from inorganic arsenic to methylated and
      dimethylated arsenicals. Here we describe a new S-adenosylmethionine
      (AdoMet)-dependent methyltransferase from rat liver cytosol that
      catalyzes the conversion of arsenite to methylated and dimethylated
      species. This 42-kDa protein has sequence motifs common to many non-
      nucleic acid methyltransferases and is closely related to
      methyltransferases of previously unknown function that have been
      identified by conceptual translations of cyt19 genes of mouse and
      human genomes. Hence, we designate rat liver arsenic
      methyltransferase as cyt19 and suggest that orthologous cyt19 genes
      encode an arsenic methyltransferase in the mouse and human genomes.
      Our studies with recombinant rat cyt19 find that, in the presence of
      an exogenous or a physiological reductant, this protein can catalyze
      the entire sequence of reactions that convert arsenite to methylated
      metabolites. A scheme linking cyt19 and thioredoxin-thioredoxin
      reductase in the methylation and reduction of arsenicals is proposed.


      A review of the enzymology of arsenic metabolism and a new potential
      role of hydrogen peroxide in the detoxication of the trivalent
      arsenic species. H Vasken Aposhian, RA Zakharyan, MD Avram, A
      Sampayo-Reyes, and ML Wollenberg. Toxicol Appl Pharmacol 1 Aug 2004
      198(3): p. 327.

      Abstract: This laboratory has studied the enzymology involved in
      the biotransformation of inorganic arsenic to dimethylarsinous acid
      (DMA(III)) and in human studies established that monomethylarsonous
      acid (MMA(III)) and DMA(III) appear in urine of people chronically
      exposed to arsenic. It appears that only two proteins are required
      for inorganic arsenic biotransformation in the human, namely,
      monomethylarsonic acid (MMA(V)) reductase and arsenic
      methyltransferase. MMA(V) reductase and the unique glutathione
      transferase omega (hGST-O) are identical proteins. Arsenicals with a
      +3 oxidation state are more toxic than the +5 species. While
      methylation of arsenite, MMA(III), and DMA(III) produces less toxic
      +5 oxidation arsenic species containing an additional methyl group
      such as MMA(V), dimethylarsinic acid (DMA(V)), and TMAO, a new
      mechanism involving hydrogen peroxide for detoxifying arsenite, MMA
      (III), and DMA(III) is proposed based on in vitro experiments.


      The role of active arsenic species produced by metabolic reduction
      of dimethylarsinic acid in genotoxicity and tumorigenesis. K
      Yamanaka, K Kato, M Mizoi, Y An, F Takabayashi, M Nakano, M Hoshino,
      and S Okada. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 385.

      Abstract: In recent research of arsenic carcinogenesis, many
      researchers have directed their attention to methylated metabolites
      of inorganic arsenics. Because of its high cytotoxicity and
      genotoxicity, trivalent dimethylated arsenic, which can be produced
      by the metabolic reduction of dimethylarsinic acid (DMA), has
      attracted considerable attention from the standpoint of arsenic
      carcinogenesis. In the present paper, we examined trivalent
      dimethylated arsenic and its further metabolites for their chemical
      properties and biological behavior such as genotoxicity and
      tumorigenicity. Our in vitro and in vivo experiments suggested that
      the formation of cis-thymine glycol in DNA was induced via the
      production of dimethylated arsenic peroxide by the reaction of
      trivalent dimethylated arsenic with molecular oxygen, but not via
      the production of common reactive oxygen species (ROS; superoxide,
      hydrogen peroxide, hydroxyl radical, etc.). Thus, dimethylated
      arsenic peroxide may be the main species responsible for the tumor
      promotion in skin tumorigenesis induced by exposure to DMA. Free
      radical species, such as dimethylarsenic radical [(CH(3))(2)As.] and
      dimethylarsenic peroxy radical [(CH(3))(2)AsOO.], that are produced
      by the reaction of molecular oxygen and dimethylarsine [(CH(3))(2)
      AsH], which is probably a further reductive metabolite of trivalent
      dimethylated arsenic, may be main agents for initiation in mouse
      lung tumorigenesis.


      Effects of protein deficient diets on the developmental toxicity of
      inorganic arsenic in mice. CA Lammon and RD Hood. Birth Defects
      Res Part B Dev Reprod Toxicol 1 Jun 2004 71(3): p. 124.

      Abstract: BACKGROUND: Inorganic arsenic, when given by injection to
      pregnant laboratory animals (mice, rats, hamsters), has been shown
      to induce malformations. Arsenic methylation may be a detoxification
      step, and diets deficient in protein are a poor source of methyl
      donors and may possibly result in impaired arsenic methylation.
      Human health effects from chronic arsenic exposure have been
      reported mainly in populations with low socioeconomic status.
      Individuals in such populations are likely to suffer from
      malnutrition, which can compromise embryonic/fetal development and
      diminish arsenic methylating capacity. We sought to determine if
      dietary protein deficiency affects the developmental toxicity of
      inorganic arsenic. METHODS: Mated females were randomly assigned to
      one of 12 treatment groups. Experimental groups received either
      AsIII or AsV i.p. on Gestation Day 8 (GD 8, plug=GD 0) and were
      maintained on a 5%, 10%, or 20% protein custom mixed diet from GD 1
      until sacrifice. Controls received the custom diets alone, were
      given AsIII or AsV i.p. on GD 8 with Teklad LM-485 rodent diet, or
      were fed the LM-485 diet alone. Test females were sacrificed on GD
      17, and their litters were examined for mortality and developmental
      defects. RESULTS: Arsenic plus dietary protein deficiency decreased
      maternal weight gain and increased the incidences of exencephaly,
      ablepharia, and skeletal defects, such as malformed vertebral
      centra, fused ribs, and abnormal sternebrae (bipartite, rudimentary,
      or unossified). CONCLUSIONS: These results demonstrate that dietary
      protein deficiency enhances the developmental toxicity of inorganic
      arsenic, possibly by impairment of arsenic methylation.


      Water intake in an Asian population living in arsenic-contaminated
      area. C Watanabe, A Kawata, N Sudo, M Sekiyama, T Inaoka, M Bae,
      and R Ohtsuka. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 272.

      Abstract: Exposure evaluation is an indispensable step for the risk
      assessment of chronic arsenic toxicity. The amount of water intake,
      which consists of the base of exposure calculation, has been lacking
      for the arsenic-affected populations in the developing countries.
      Thus, the purposes of the present study were (1) to estimate the
      water intake in such population, and (2) to estimate the relative
      importance of water versus food as the source of arsenic exposure.
      Adult males and females (n = 19 for each) were selected from two
      rural Bangladeshi communities that entirely depended on tubewells
      for their water supply. Their water intake was measured by two
      methods, a 24-h self-report and an interview with frequent visits.
      Results of the two methods generally agreed with each other in terms
      of correlation and the absolute intakes. Mean water intake obtained
      by the self-report method was found to be around 3 l/day with
      substantial individual variation (the maximum = 6 l/day), no sex
      difference, and a significant between-community difference. The
      calculation for total arsenic exposure demonstrated that there was
      no sex difference in arsenic exposure except when the exposure was
      mainly from food and thus relatively low. Although these results
      need to be further confirmed under various environmental settings,
      these results suggested that (1) the sex difference in the
      manifestation of arsenic toxicity previously observed in this area
      should be related with factors other than exposure level and that
      (2) the risks associated with low arsenic concentrations of
      groundwater should be carefully interpreted because food may be
      providing additional burden of arsenic.


      Arsenic toxicity at low doses: epidemiological and mode of action
      considerations. A Schoen, B Beck, R Sharma, and E Dube. Toxicol
      Appl Pharmacol 1 Aug 2004 198(3): p. 253.

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


      Distributions and chemical forms of arsenic after intravenous
      administration of dimethylarsinic and monomethylarsonic acids to
      rats. KT Suzuki, A Katagiri, Y Sakuma, Y Ogra, and M Ohmichi.
      Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 336.

      Abstract: The observed toxicity of arsenic is highly dependent on
      animal species and differences in metabolism. Rats are one of the
      most tolerant species, and the metabolic pathway is quite different
      in some aspects from those of other mammals. The distinct metabolic
      pathway including the preferential accumulation in red blood cells
      (RBCs) has been explained, whereby allowing an effective use of rats
      as an animal model for the arsenic metabolism. In the present study,
      distributions of arsenic among organs/tissues/body fluids and their
      chemical forms were studied after intravenous injection of arsenic
      in the forms of dimethylarsinic (DMA(V)) and monomethylarsonic acids
      (MMA(V)) to rats. DMA(V) and MMA(V) were mostly excreted into urine
      immediately after the injection as the intact forms, and both forms
      were taken up less effectively by organs/tissues than arsenite. The
      methylated arsenics distributed in organs/tissues were excreted
      directly into urine and excreted before being redistributed in RBCs.
      DMA(V) and MMA(V) taken up by the liver were transformed to
      metabolites not yet identified, accumulated transiently in the
      liver, and then they disappeared from the liver. The unidentified
      metabolites were assumed to be transformed from dimethylarsinic acid
      (DMA(III)) following the consecutive metabolic reactions [MMA(V) -->
      monomethylarsonous acid (MMA(III)) --> DMA(V) --> DMA(III)]. The
      unidentified metabolites were excreted not into the bile but into
      the bloodstream. Injections of DMA(V) and MMA(V) induced a biliary
      excretion of arsenic but only at 0.2-0.3% of the dose, the arsenic
      in the bile being their intact free forms.


      Arsenic contamination and arsenicosis in China. G Sun. Toxicol
      Appl Pharmacol 1 Aug 2004 198(3): p. 268.

      Abstract: Arsenicosis is a serious environmental chemical disease
      in China mainly caused by drinking water from pump wells
      contaminated by high levels of arsenic. Chronic exposure of humans
      to high concentrations of arsenic in drinking water is associated
      with skin lesions, peripheral vascular disease, hypertension,
      blackfoot disease, and high risk of cancers. Lead by the Ministry of
      Health of China, we carried out a research about arsenicosis in
      China recently. Areas contaminated with arsenic from drinking water
      are determined by 10% pump well water sample method while areas from
      burning coal are determined by existing data. Two epidemic areas of
      Shanxi Province and Inner Mongolia are investigated for the
      distribution of pump wells containing high arsenic. Well water in
      all the investigated villages of Shanxi Province showed polluted by
      high arsenic, and the average rate of unsafe pump well water is 52%.
      In Inner Mongolia, the high percentage of pump wells containing
      elevated arsenic is found only in a few villages. The average rate
      of unsafe pump well water is 11%. From our research, we find that
      new endemic areas are continuously emerging in China. Up to now,
      epidemic areas of arsenicosis mainly involve eight provinces and 37
      counties in China. In the affected areas, the discovery of wells and
      coal with high levels of arsenic is continuing sporadically, and a
      similar scattered distribution pattern of patients is also being


      Arsenic speciation in human urine: are we all the same? VW Lai, Y
      Sun, E Ting, WR Cullen, and KJ Reimer. Toxicol Appl Pharmacol 1 Aug
      2004 198(3): p. 297.

      Abstract: We studied the arsenic speciation in human urine samples
      by using high-performance liquid chromatography-inductively coupled
      plasma-mass spectrometry (HPLC-ICP-MS). We investigated the arsenic
      speciation in the urine collected from nine volunteers during a 3-
      day period after a meal of blue mussels, Mytilus edulis. We also
      studied the effect of cooking on the arsenic speciation.
      Arsenobetaine and dimethylarsinic acid (DMAA) were the major arsenic
      metabolites found in the urine samples. Significant amounts of
      unknown metabolites were also detected. The excretion patterns of
      arsenic from individuals were generally similar except for two
      subjects. One of whom excreted high amounts of arsenobetaine even
      though no arsenic-rich food was eaten for 3 days before the
      experiment. The results reveal that we need a better understanding
      of the metabolism of arsenic compounds by human.


      Molecular basis for arsenic-induced alteration in nitric oxide
      production and oxidative stress: implication of endothelial
      dysfunction. Y Kumagai and J Pi. Toxicol Appl Pharmacol 1 Aug 2004
      198(3): p. 450.

      Abstract: Accumulated epidemiological studies have suggested that
      prolonged exposure of humans to arsenic in drinking water is
      associated with vascular diseases. The exact mechanism of how this
      occurs currently unknown. Nitric oxide (NO), formed by endothelial
      NO synthase (eNOS), plays a crucial role in the vascular system.
      Decreased availability of biologically active NO in the endothelium
      is implicated in the pathophysiology of several vascular diseases
      and inhibition of eNOS by arsenic is one of the proposed mechanism s
      for arsenic-induced vascular diseases. In addition, during exposure
      to arsenic, overproduction of reactive oxygen species (ROS) can
      occur, resulting in oxidative stress, which is another major risk
      factor for vascular dysfunction. The molecular basis for decreased
      NO levels and increased oxidative stress during arsenic exposure is
      poorly understood. In this article, evidence for arsenic-mediated
      alteration in NO production and oxidative stress is reviewed. The
      results of a cross-sectional study in an endemic area of chronic
      arsenic poisoning and experimental animal studies to elucidate a
      potential mechanism for the impairment of NO formation and oxidative
      stress caused by prolonged exposure to arsenate in the drinking
      water are also reviewed.


      Understanding arsenic carcinogenicity by the use of animal models.
      H Wanibuchi, EI Salim, A Kinoshita, J Shen, M Wei, K Morimura, K
      Yoshida, K Kuroda, G Endo, and S Fukushima. Toxicol Appl Pharmacol
      1 Aug 2004 198(3): p. 366.

      Abstract: Although numerous epidemiological studies have indicated
      that human arsenic exposure is associated with increased incidences
      of bladder, liver, skin, and lung cancers, limited attempts have
      been made to understand mechanisms of carcinogenicity using animal
      models. Dimethylarsinic acid (DMA), an organic arsenic compound, is
      a major metabolite of ingested inorganic arsenics in mammals. Recent
      in vitro studies have proven DMA to be a potent clastogenic agent,
      capable of inducing DNA damage including double strand breaks and
      cross-link formation. In our attempts to clarify DMA
      carcinogenicity, we have recently shown carcinogenic effects of DMA
      and its related metabolites using various experimental protocols in
      rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a
      two-stage promotion bioassay by DMA of rat urinary bladder and liver
      carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats;
      (4) studies on the effects of DMA on lung carcinogenesis in rats;
      (5) promotion of skin carcinogenesis by DMA in keratin
      (K6)/ornithine decarboxylase (ODC) transgenic mice; (6)
      carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA
      glycolase (OGG1) mutant mice; (7) promoting effects of DMA and
      related organic arsenicals in rat liver; (8) promoting effects of
      DMA and related organic arsenicals in a rat multi-organ
      carcinogenesis test; and (9) 2-year carcinogenicity tests of
      monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in
      rats. The results revealed that the adverse effects of arsenic
      occurred either by promoting and initiating carcinogenesis. These
      data, as covered in the present review, suggest that several
      mechanisms may be involved in arsenic carcinogenesis.


      Incidence of Transitional Cell Carcinoma of the Bladder and Arsenic
      Exposure in New Hampshire. Margaret R. Karagas, Tor D. Tosteson, J.
      Steven Morris, Eugene Demidenko, Leila A. Mott, John Heaney, and
      Alan Schned. Cancer Causes Control 1 Jun 2004 15(5): p. 465.

      Abstract: Objective : Arsenic is a known bladder carcinogen and
      populations exposed to high arsenic levels in their water supply
      have reported elevated bladder cancer mortality and incidence rates.
      To examine the effects of lower levels of arsenic exposure on
      bladder cancer incidence, we conducted a case-control study in New
      Hampshire, USA where levels above 10 micro/l are commonly found in
      private wells. Methods : We studied 383 cases of transitional cell
      carcinoma of the bladder cancer, newly diagnosed between July 1,
      1994 and June 30, 1998 and 641 general population controls.
      Individual exposure to arsenic was determined in toenail clippings
      using instrumental neutron activation analysis. Results : Among
      smokers, an elevated odds ratio (OR) for bladder cancer was observed
      for the uppermost category of arsenic (OR: 2.17, 95% CI: 0.92-5.11
      for greater than 0.330 mcg/g compared to less than 0.06 micro/g).
      Among never smokers, there was no association between arsenic and
      bladder cancer risk. Conclusions : These, and other data, suggest
      that ingestion of low to moderate arsenic levels may affect bladder
      cancer incidence, and that cigarette smoking may act as a co-


      Arsenic toxicity in mice and its possible amelioration. RJ Verma, A
      Vasu, and AA Saiyed. J Environ Sci (China) 1 Jan 2004 16(3): p.

      Abstract: Oral administration of arsenic trioxide (3 and 6 mg/kg
      body weight/d) for 30 d caused, as compared with vehicle control,
      dose-dependent significant reductions in body weight, absolute
      weight, protein, glycogen, as well as, total, dehydro and reduced
      ascorbic acid contents both in the liver and kidney of arsenic-
      treated mice. Succinic dehydrogenase (SDH) and phosphorylase only in
      the liver activities were significantly reduced in a dose-dependent
      manner. Acid phosphatase activity was significantly decreased in the
      liver of low dose arsenic-treated animals; however, significant rise
      in its activity was observed in high dose group. As compared with
      vehicle control, treatment also caused significant dose-dependent
      reductions in SDH, alkaline phosphatase and acid phosphatase
      activities in the kidney of mice. Vitamin E cotreatment as well as,
      30 d withdrawal of arsenic trioxide treatment with or without
      vitamin E caused significant amelioration in arsenic-induced
      toxicity in mice. Administration of vitamin E during withdrawal of
      treatment also caused significant amelioration as compared from only
      withdrawal of the treatment. It is concluded that vitamin E
      ameliorates arsenic-induced toxicities in the liver and kidney of


      Role of oxidative damage in the genotoxicity of arsenic. TK Hei and
      M Filipic. Free Radic Biol Med 1 Sep 2004 37(5): p. 574.

      Abstract: Arsenic is a well-established human carcinogen and is
      ubiquitous in the environment. For decades, arsenic has been
      considered to be a nongenotoxic carcinogen because it is only weakly
      active or, more often, completely inactive in bacterial and
      mammalian cell mutation assays. In this review, evidence is
      presented that when assayed using model systems in which both
      intragenic and multilocus mutations can readily be detected, arsenic
      is, indeed, found to be a strong, dose-dependent mutagen which
      induces mostly multilocus deletions. Furthermore, the roles of
      reactive oxygen and reactive nitrogen species in mediating the
      genotoxic response are presented in a systematic and logical fashion
      in support of a working model. The data suggest that antioxidants
      may be a useful interventional treatment in reducing the deleterious
      effects of arsenic.


      Speciation of arsenic in biological samples. BK Mandal, Y Ogra, K
      Anzai, and KT Suzuki. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p.

      Abstract: Speciation of arsenicals in biological samples is an
      essential tool to gain insight into its distribution in tissues and
      its species-specific toxicity to target organs. Biological samples
      (urine, hair, fingernail) examined in the present study were
      collected from 41 people of West Bengal, India, who were drinking
      arsenic (As)-contaminated water, whereas 25 blood and urine samples
      were collected from a population who stopped drinking As
      contaminated water 2 years before the blood collection. Speciation
      of arsenicals in urine, water-methanol extract of freeze-dried red
      blood cells (RBCs), trichloroacetic acid treated plasma, and water
      extract of hair and fingernail was carried out by high-performance
      liquid chromatography (HPLC)-inductively coupled argon plasma mass
      spectrometry (ICP MS). Urine contained arsenobetaine (AsB, 1.0%),
      arsenite (iAs(III), 11.3), arsenate (iAs(V), 10.1),
      monomethylarsonous acid (MMA(III), 6.6), monomethylarsonic acid (MMA
      (V), 10.5), dimethylarsinous acid (DMA(III), 13.0), and
      dimethylarsinic acid (DMA(V), 47.5); fingernail contained iAs(III)
      (62.4%), iAs(V) (20.2), MMA(V) (5.7), DMA(III) (8.9), and DMA(V)
      (2.8); hair contained iAs(III) (58.9%), iAs(V) (34.8), MMA(V) (2.9),
      and DMA(V) (3.4); RBCs contained AsB (22.5%) and DMA(V) (77.5); and
      blood plasma contained AsB (16.7%), iAs(III) (21.1), MMA(V) (27.1),
      and DMA(V) (35.1). MMA(III), DMA(III), and iAs(V) were not found in
      any plasma and RBCs samples, but urine contained all of them.
      Arsenic in urine, fingernails, and hair are positively correlated
      with water As, suggesting that any of these measurements could be
      considered as a biomarker to As exposure. Status of urine and
      exogenous contamination of hair urgently need speciation of As in
      these samples, but speciation of As in nail is related to its total
      As (tAs) concentration. Therefore, total As concentrations of nails
      could be considered as biomarker to As exposure in the endemic areas.


      Arsenic and atherosclerosis. PP Simeonova and MI Luster. Toxicol
      Appl Pharmacol 1 Aug 2004 198(3): p. 444.

      Abstract: Epidemiological studies have demonstrated a correlation
      between environmental or occupational arsenic exposure and a risk of
      vascular diseases related to atherosclerosis. Studies summarized in
      this review suggest that arsenic induces endothelial dysfunction,
      including inflammatory and coagulating activity as well as impairs
      nitric oxide (NO) balance. This may provide the pathophysiological
      basis for atherogenic potential of arsenic. Consistent with these
      data, arsenic accelerates atherosclerosis in apolipoprotein E (ApoE)
      deficient mice, a model of human atherosclerosis.


      Arsenic and urinary bladder cell proliferation. MI Luster and PP
      Simeonova. Toxicol Appl Pharmacol 1 Aug 2004 198(3): p. 419.

      Abstract: Epidemiologic studies have demonstrated that a close
      association exists between the elevated levels of arsenic in
      drinking water and the incidence of certain cancers, including
      transitional cell carcinomas of the urinary bladder. We have
      employed in vitro and in vivo models to examine the effects of
      sodium arsenite on the urinary bladder epithelium. Mice exposed to
      0.01% sodium arsenite in drinking water demonstrated
      hyperproliferation of the bladder uroepithelium within 4 weeks after
      initiating treatment. This occurred in the absence of amorphous
      precipitates and was accompanied by the accumulation of trivalent
      arsenite (iAs(3+)), and to a lesser extent dimethylarsenic (DMA),
      arsenate (iAs(5+)), and monomethylarsenic (MMA) in bladder tissue.
      In contrast to the bladder, urinary secretion was primarily in the
      form of DMA and MMA. Arsenic-induced cell proliferation in the
      bladder epithelium was correlated with activation of the MAP kinase
      pathway, leading to extracellular signal-regulated kinase (ERK)
      kinase activity, AP-1 activation, and expression of AP-1-associated
      genes involved in cell proliferation. Activation of the MAP kinase
      pathway involved both epidermal growth factor (EGF) receptor-
      dependent and -independent events, the latter involving Src
      activation. Studies summarized in this review suggest that arsenic
      accumulates in urinary bladder epithelium causing activation of
      specific signaling pathways that lead to chronic increased cell
      proliferation. This may play a non-epigenetic role in carcinogenesis
      by increasing the proliferation of initiated cells or increasing the
      mutational rate.

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