These dosimetric data have supported development of several pharmacokinetic models for humans and other species El-Masri and Kenyon, ; Evans et al. Such models are useful for estimating tissue exposures and can be used in risk assessment Liao et al. Three decades ago, the biochemical reactions underlying arsenic methylation were unknown. Wood formally stated this chemical scheme for arsenic methylation in a review of toxic element methylation processes.
Early work on formation of methylated arsenicals in mammals used tissue homogenates and subcellular fractions to explore the requirements for in vitro methylation. Buchet and Lauwerys showed addition of S-adenosylmethionine AdoMet and glutathione GSH to reaction mixtures containing rat liver cytosol supported conversion of inorganic arsenic to methylated products.
Focus on AdoMet as a methyl group donor for arsenic methylation was consistent with the then-contemporary finding that enzymatically catalyzed methylation of selenium used AdoMet for methyl group donation Mozier et al.
It was likely to be a cytosolic AdoMet-dependent methyltransferase that required the presence of a reductant. Although it was unclear whether the reductant protected the enzyme against oxidation or functioned as a cofactor in enzyme catalysis, an absolute requirement for a reductant imposed a number of limitations on any strategy used to isolate and characterize the protein.
Purification of a mammalian arsenic methyltransferase was the object of intensive research in the s. The presence of a monothiol e. In related work, Lin et al. A partial amino acid sequence of this protein showed that it was the product of the cyt19 gene previously annotated as a methyltransferase of unknown function. Mouse As3mt proved to be a prototype for arsenic methyltransferases in many genomes.
Genes encoding proteins closely related to mouse As3mt occur in genomes of organisms ranging from sea squirts to humans Thomas et al. These proteins share conserved sequences commonly found in nonnucleic acid methyltransferases and cysteinyl residues required for catalytic function as an arsenic methyltransferase Fomenko et al.
Given differences in molecular masses of proteins isolated from rabbit liver and mouse liver, they are unlikely to be identical. In the absence of full sequencing of the rabbit liver protein, it has proven difficult to pursue the characteristics of this putative arsenic methyltransferase.
Indeed, subsequent research has focused on the role of As3mt and its protein products in the metabolism of arsenicals. Although the presence of GSH in buffers preserved enzymatic activity during purification, dithiol-containing reductants thioredoxin, Tx; glutaredoxin, Gx; reduced lipoic acid, LA were found to support high rates of catalysis in vitro by recombinant rat As3mt Waters et al. Although GSH modulated production of mono-, di-, and trimethylated arsenicals from inorganic arsenic, it could be replaced by Tx, Gx, or LA, indicating that its presence was not required for catalysis Waters et al.
These findings suggested that redox cycling of physiological dithiol-containing reductants was required for catalytic activity of As3mt. The fusing of two intimately related catalytic functions in one enzyme would assure that metabolic transformation proceeded without accumulation of reactive and toxic intermediates.
Notably, there is evidence for separate pathways for reduction of pentavalent arsenic to trivalent arsenic in mammalian cells. Whether GSTO contributes significantly to arsenic reduction in intact organisms is unclear; studies in GSTO knockout mice failed to detect differences in patterns of arsenic methylation and excretion Chowdhury et al.
Phosphorolytic-arsenolytic enzymes such as purine nucleoside phosphorylase PNP can function as catalysts in reaction schemes in which an activated arsenate ester is reduced by thiols to arsenite Gregus et al. Existence of several mechanisms for reduction of pentavalent arsenic could be an example of functional redundancy in which independent processes mediate a single important biochemical reaction Wang and Zhang, Understanding interrelations between catalysis of methylation and of reduction in the cell will be critical to more fully comprehend the molecular basis for arsenic metabolism.
Studies in which altered As3mt expression leads to changes in capacity for arsenic methylation confirm its critical role. Heterologous expression of rat As3mt in human uroepithelial cells that do not methylate arsenic confers capacity to methylate arsenic Drobna et al. Silencing of AS3MT expression in human hepatoma cells by RNA interference diminishes, but does not eliminate, capacity to methylate arsenic Drobna et al.
The fate of arsenic differs radically in As3mt knockout mice and wild-type mice. Following single or repeated oral doses of arsenate, tissues from As3mt knockout mice attain higher concentrations of inorganic arsenic than do those from wild-type mice and the rate of whole body clearance of arsenic is much slower in knockout than in wild-type mice Drobna et al. A lower rate of whole body clearance of inorganic arsenic and its methylated metabolites in As3mt knockout mice is consistent with earlier findings that methylated and dimethylated arsenic clear faster than inorganic arsenic Buchet et al.
These phenotypic changes in As3mt knockout mice are also associated with increased susceptibility to damage to the uroepithelial cells following exposure to inorganic arsenic Yokohira et al. Capacity to produce methylated metabolites of inorganic arsenic can depend on environmental or genetic factors. For example, environmental factors such as selenium nutriture or protein and lipotrope deficiency affect patterns of urinary metabolites in mice treated with inorganic arsenic Kenyon et al.
Similarly, there is evidence that genotypic variation in the AS3MT gene in humans alters the capacity to methylate inorganic arsenic. Changes in the capacity to methylate inorganic arsenic can be referred to as the arsenic methylation phenotype. Thus, it is possible to look for connections between AS3MT genotype and arsenic methylation phenotype. A linkage between AS3MT genotype and arsenic methylation phenotype was first noted in a study of arsenite metabolism by cultured primary human hepatocytes Drobna et al.
This genotypic difference was associated with an altered arsenic methylation phenotype. Cells from the affected donor showed a higher capacity for production of monomethylarsenic at medium concentrations of arsenite compared with cells from donors homozygous for wild-type AS3MT which showed reduced mono- and dimethylarsenic production. In populations worldwide, the nonsynonymous single nucleotide polymorphism SNP for the MT mutation occurs at an allele frequency of 0.
Population-based studies have shown that MT genotype and genotype differences at other exonic and intronic sites affect arsenic methylation phenotype. The concept of genotype-phenotype correlations can be extended to determine if changes in AS3MT genotype can be linked to evidence of altered susceptibility to adverse health effects associated with chronic exposure to inorganic arsenic.
This finding suggests that persistently high levels of monomethylarsenic in urine related to the MT genotype are associated with increased cancer risk. Taken together, these studies show that the MT genotype that affects the arsenic methylation phenotype can also be associated with increased risk of either noncancer or cancer health effects. Additional studies will show whether other AS3MT polymorphisms produce these or other phenotypic effects.
The effects of polymorphisms in AS3MT should be evaluated in the context of polymorphisms in other genes that may affect the arsenic methylation phenotype or influence susceptibility to the adverse health effects associated with chronic exposure to inorganic arsenic. An exon 3 polymorphism in PNP, a putative arsenate reductase, increases the risk of skin cancer in individuals exposed to inorganic arsenic in drinking water De Chaudhuri et al.
Associations have been identified between polymorphisms in several genes encoding members of the GSH transferase GST family and urinary metabolite profiles or risk for arsenic-induced cancers Lin et al. Although the single-gene strategy for identifying modifiers is effective, a more heuristic approach to understanding the role of genes in control of arsenic metabolism and toxicity has looked for haplotypes associated with altered metabolism or response.
A LD cluster on human chromosome 10 near the AS3MT locus indicates that several genes may be acting to modify the arsenic methylation phenotype or to alter susceptibility Gomez-Rubio et al. Further studies of gene associations and of the role of members of the LD cluster will be needed to identify the modifiers.
Although this review has focused on metabolism of arsenicals mediated by the host organism, particularly the central role of AS3MT as a determinant of metabolic capacity and susceptibility, the organisms that compose the microbiome of the gastrointestinal tract also have the capacity to convert inorganic arsenic to methylated species.
The microbiome of the human gastrointestinal tract consists of nearly times as many cells as does the body of the host and contains about 3-times as many genes as does the human genome Zhu et al. Given the size and genetic diversity of organisms of the gut microbiome, it is probably not surprising that a complex interaction has evolved between these cells and cells that constitute the host component of the gastrointestinal system Spor et al.
Evidence for a role of the microbiota of the gastrointestinal tract in the metabolism of arsenicals comes primarily from in vitro studies in which the microbiota of the mouse cecum is incubated under strictly anaerobic conditions with arsenicals. Studies with arsenate and DMAs V found that these arsenicals were rapidly converted to methylated metabolites Kubachka et al. In addition to oxyarsenical metabolites, the products of these reactions included thioarsenicals in which O is replaced with S.
The prevalence of thioarsenicals among the products of metabolism of anaerobic microorganisms presumably reflects low O tension and the abundance of H 2 S in cultures. In terms of risk, the significance of metabolism of arsenic by the microbiota of the gastrointestinal tract preabsorptive metabolism depends on whether the bioavailabilities of the metabolites are materially different from those of the parent compounds.
Additional studies are needed to resolve this issue. Over the past half century, the study of arsenic metabolism has progressed from descriptive studies of kinetic behavior of inorganic arsenic and its metabolites to an effort to understand the molecular basis of metabolism and the interactions among genes that affect the capacity for metabolism and modify the biological response to this arsenic.
It has recently been suggested that arsenic is a toxicant that could profitably be studied by newly available techniques in genomics, metabolomics, and proteomics Vlaanderen et al. It will be interesting to see what new insights these technologies will bring to our understanding of arsenic metabolism and toxicity. The precise MOA for the many disease endpoints following acute and chronic arsenic exposure are not known, although research in this area has been ongoing for many years.
A clear understanding of the MOA for arsenic, indeed for any toxic chemical, will facilitate selection of the appropriate human risk assessment model e. The most appropriate dose-response model for low environmental exposures to arsenic is the subject of debate.
Trivalent arsenicals e. Several proposed MOA for arsenic and examples of the biochemical effects that occur are shown in Figure 2. Proposed MOA for arsenic and examples of biochemical effects that result from this action. The chemistry of arsenic is an important aspect of its MOA. Observations in the late 19th century noted that arsenic exists in the body in pentavalent and trivalent oxidation states and that it interacts with sulfur Parascandola, One of the first proposed MOAs for arsenic, suggested by Binz and Schulz in Parascandola, , was the interference of cellular oxidation from the cycling of oxygen during the interconversion of arsenate and arsenite.
This would suggest that both arsenicals are equally potent, but as it became apparent, arsenite is more potent than arsenate, so this proposal was soon disfavored. Early mechanistic studies centered on an aromatic arsenic compound used to treat syphilis and trypanosomiasis.
See Riethmiller, for a review of the discovery of Salvarsan and Lloyd et al. Ehrlich proposed that the chemotherapeutic toxic effect of Salvarsan involved its binding to a chemoreceptor in the microorganism and that this receptor might contain a hydroxyl or sulfhydryl group Parascandola, Carl Voegtlin and colleagues conducted a series of studies investigating the MOA of Salvarsan and similarly structured arsenicals reviewed in Voegtlin Voegtlin et al.
In vitro and in vivo studies showed that glutathione and other sulfyhydryl compounds such as cysteine and thioglycollate antagonized the trypanocidal effect of arsenoxide. Chemicals without a sulfhydryl group, such as glucose, were ineffective. A general hypothesis in the s and s was that toxic chemicals selectively inhibited enzymes, which would lead to a pathologic effect. Rudolph Peters and colleagues Peters et al.
Peters et al. Previously, Cohen et al. It was thought that excess monothiols could reverse the effect of arsenic on pyruvate oxidation. However, monothiols such as glutathione were ineffective antagonists. Stocken and Thompson incubated kerateine, a form of keratin with the disulfide linkages reduced forming free sulfhydryl groups with lewisite and arsenite. It was determined that the arsenic in lewisite was bound to two thiol groups, forming a stable 5-membered ring, whereas arsenite was bound to only one sulfhydryl group.
From this work, a dithiol antidote to lewisite, 2,3-dimercaptopropanol British anti-lewisite, BAL was developed. Later it was determined that in the pyruvate oxidase system later termed the pyruvate dehydrogenase complex [PDH] , that lipoic acid, which contains vicinal dithiols, was the sensitive moiety to which arsenicals would bind. Although arsenite can inhibit PDH by binding to vicinal sulfhydryl groups within this enzyme, as does phenylarsine oxide, studies by Samikkannu et al.
This occurs at concentrations of arsenite much lower than concentrations required for inhibition by direct binding to the sulfhydryl group. Arsenate was observed to affect in vitro phosphate turnover in the early s Harden, Over the years, additional in vitro studies have shown that arsenate has inherent toxicological properties because of its interaction with phosphate.
However, it is not known if there are in vivo effects that are a result of this interaction between arsenate and phosphate. Arsenic and phosphorus are in Group 15 of the periodic table nitrogen or nitrogen group and have similar physicochemical properties.
Arsenic acid H 3 AsO 4 and phosphoric acid H 3 PO 4 , the fully protonated forms of arsenate and phosphate, respectively, have comparable structure and similar acid dissociation constants. Because of their similar properties, arsenate can substitute for phosphate in several biochemical reactions Dixon, Like phosphate, arsenate forms ester linkages with its hydroxyl groups.
Arsenolysis can occur during glycolysis and oxidative phosphorylation in the presence of arsenate Crane and Lipmann, ; Gresser, In the glycolytic pathway, arsenate can form the intermediate anhydride, 3-phosphoglyceroyl arsenate.
Both reactions form unstable arsenate anhydrides, which hydrolyze easily. The overall result is that formation of ATP is diminished. At the cellular level, arsenate depletes ATP in rabbit Delnomdedieu et al. The human erythrocytes died a few hours after arsenic exposure, presumably because of the loss of both ATP and plasma membrane integrity. Arsenite is ineffective in depleting ATP in human erythrocytes.
The formation of reactive oxygen and nitrogen species by arsenic is one of the most studied MOAs for arsenic toxicity today Hughes and Kitchin, ; Kitchin and Ahmad, ; Kitchin and Conolly, ; Lantz and Hays, ; Shi et al.
ROS formed by arsenic are involved in several of the proposed MOAs including genotoxicity, signal transduction, cell proliferation, and inhibition of DNA repair. Reactive species are formed in vitro and in vivo in the presence of arsenic and include superoxide anion, hydroxyl radical, hydrogen peroxide, reactive nitrogen species, and arsenic-centered and arsenic peroxyl radicals Kitchin ; Shi et al.
Several studies have shown that the addition of antioxidants and radical scavengers decrease arsenic-induced ROS formation and related toxicity Shi et al. However, this antagonism is not always observed in vivo Wei et al.
The mechanism of ROS formation by arsenic is not clear. It may occur during oxidation of arsenite to arsenate Del Razo et al. Reports on the genotoxic effects of arsenic were first published in the mids. However, in this same study, arsenite did not induce tryptophan reversions in Escherichia coli strains. Most studies published since the s indicate that arsenic does not directly interact with DNA to cause point mutagens in bacterial or mammalian reversion assays Basu et al.
However, arsenic is comutagenic. Arsenite enhances the mutagenic effect of ultraviolet UV radiation in bacterial Rossman, and mammalian cells Li and Rossman, and that of direct-acting mutagens such as methyl methansulfonate Lee et al. Although not directly mutagenic, arsenic is genotoxic, inducing effects including deletion mutations, oxidative DNA damage, DNA strand breaks, sister chromatid exchanges, chromosomal aberrations, aneuploidy, and micronuclei Basu et al.
Other effects of arsenic related to genotoxicity include gene amplification, transforming activity, and genomic instability Rossman, These genotoxic effects of arsenic are observed in vitro in mammalian cells and in vivo in laboratory animals and humans Basu et al.
For example, Beckman et al. Trivalent arsenicals, both inorganic and organic, are more potent genotoxins than the pentavalent arsenicals Kligerman et al. The mechanism of genotoxic action of arsenic may result from generation of ROS, inhibition of DNA repair, and altered DNA methylation that may lead to genomic instability Rossman, Arsenic inhibits DNA repair in bacterial and mammalian cells.
This inhibitory effect may account for the cogenotoxic effect of arsenic with N-methyl-N-nitrosourea and UV radiation Rossman, One of the first studies examining the effect of arsenic on DNA repair used strains of E. Cells were exposed to UV radiation and then plated with or without arsenite.
Cells competent for postreplicative DNA repair in the presence of arsenite were the most sensitive to the lethal effects of UV radiation. In a small group of individuals exposed to arsenic in drinking water, toenail arsenic levels a biomarker of arsenic exposure were inversely correlated with the expression of three NER genes Andrew et al. The catalytic function of zinc finger containing proteins depends on binding of zinc to cysteinyl residues. Arsenic may disrupt protein function by displacing zinc from its binding site or by inactivating the sulfhydryl groups of cysteine by oxidation.
In a recent review, Gentry et al. They analyzed data on in vitro cellular and in vivo gene expression changes following exposure to inorganic arsenic.
The analysis of the data suggests the key events in carcinogenicity of arsenic include inhibition of DNA repair under conditions of oxidative stress, inflammation, and proliferative signaling. This may lead to a condition in which mitosis proceeds without maintaining the integrity of the cellular DNA. Signal transduction pathways transmit extracellular signals, via an intracellular series of signaling molecules e. Cellular processes such as proliferation, differentiation, and apoptosis are directed and managed by these pathways or cascades.
Arsenic can alter signal transduction, which leads to activation or inhibition of transcription factors, regulatory proteins which bind to DNA and regulate gene transcription Bode and Dong, ; Druwe and Vaillancourt, ; Huang et al. In the s, some of the first studies examining the effects of arsenic on signal transduction were published. Rouse et al. Liu et al. The activation process appeared to involve generation of oxidative stress, as the free radical scavenger N-acetylcysteine inhibited activation of the kinases Liu et al.
Arsenite activates JNK and p38 in HeLa cells, which in turn stimulates AP-1 transcriptional activity, leading to increased expression of the proto-oncogenes c-jun and c-fos Cavigelli et al. In mice exposed to arsenite in drinking water, activation of the MAPK pathway was correlated with hyperproliferation of bladder epithelium Luster and Simeonova, This appeared to result from increased activation of AP-1 followed by expression of APrelated genes that have a role in cell proliferation.
The pathway for this activation appears to involve c-Src and epidermal growth factor receptor EGFR signaling cascades Simeonova et al. MAP kinases, ERK, and p38 are not activated at these levels in the endothelial cells but at higher concentrations that can result in cell death.
More recently, Andrew et al. In human lung tumor biopsies, levels of phosphorylated EGFR were higher in specimens from subjects with elevated toenail arsenic levels compared with those with lower exposures.
Barchowsky et al. Nrf2, by regulating gene expression, controls the cellular antioxidant response to exogenous insult. Activation of Nrf2 in vitro by tert -butylhydroquinone tBHQ and sulforaphone SF can protect a cell from trivalent arsenic-induced toxicity Wang et al. Nrf2 null mice are more susceptible to arsenite-induced liver and bladder toxicity than Nrf2 homozygous mice Jiang et al. Wang et al. Arsenic is well known for its carcinogenic properties, but interestingly, this metalloid is also used to treat a specific form of cancer.
Arsenic trioxide which solubilizes to arsenite in water is a treatment for cancer patients with all trans-retinoic acid-resistant acute promyelocytic leukemia Bode and Dong, ; Platanias, Arsenic trioxide generates ROS, which activates JNK and upregulates pro-apoptotic proteins and downregulates anti-apoptotic proteins.
Thus, the leukemic cells undergo arsenic-induced apoptosis and the patients enter a state of remission to the cancer. However, the cancer treatment with arsenic needs to be carefully monitored because of its acute toxicological effects.
A hallmark of arsenic toxicity in humans is hyperkeratosis. Cells may proliferate from mitogenic stimuli or compensatory regeneration due to cell toxicity and death Cohen and Ellwein, Germolec and colleagues in the s observed that inorganic arsenic stimulates overexpression of growth factors that could potentially mediate skin neoplasia.
These cells also proliferate in the presence of arsenite. The skin of Tg. AC mice transgenic mouse, see below for details displays hyperkeratosis following a week drinking water exposure to arsenite ppm. More recently, Waalkes et al. Rac1 is a signaling G protein that regulates the cell cycle, maintains epidermal stem cells, and other cellular processes.
Rac1 gene transcripts and its protein are overexpressed in skin and tumors of Tg. AC mice treated with arsenite during gestation days 8—18 followed by topical application of TPA through adulthood. The results suggest that the cancer response is associated with distorted signaling between skin tumor stem cells and altering population dynamics. Rac1 also appears to have a role in arsenite-induced NADPH oxidase generation of oxidants in porcine aortic endothelial cells Smith et al.
The rat bladder urothelium shows increased cytotoxicity and cell proliferation following exposure to DMAs V in drinking water Wanibuchi et al. Both studies showed increased bromodeoxyuridine labeling index, which is indicative of cell proliferation.
The cytotoxicity and hyperplasia of the urothelium were reversible after removal of dietary DMAs V. Morphological examination of the rat urothelium following treatment of rats with dietary DMAs V ppm for 1—3 days showed focal cellular necrosis and after 7 days widespread necrosis Cohen et al.
Increased cell proliferation was observed in the urothelium after 7 days of exposure to DMAs V. Coadministering 2,3-dimercaptopropanesulfonic acid, a chelator of trivalent arsenic, in the diet with DMAs V to rats inhibited the necrosis and regenerative proliferation of the urothelium Cohen et al.
In vitro studies with rat urothelial cells suggest that the cytotoxicity of trivalent arsenicals may be a result of, at least in part, oxidative damage Wei et al. Simeonova et al. After 16 weeks of exposure to arsenite, the hyperplasia was accompanied by an increase in DNA binding of the activating protein AP -1 transcription factor and inorganic arsenic in bladder tissue. A follow-up study by Simeonova et al. More recent work in As3mt knockout mice Yokohira et al.
Epigenetic mechanisms such as altered DNA methylation have a role in arsenic toxicity and carcinogenicity. Gene transcription is regulated by DNA methylation. In the late s, two separate laboratories reported that arsenic alters DNA methylation, with both hypo- and hypermethylation of DNA observed. Zhao et al. Mass and Wang observed hypermethylation of a portion of the p53 promoter region of human lung adenocarcinoma A cells treated with arsenite. The tumor suppressor protein p53 has a role in cell cycle regulation.
Inhibition of its expression by hypermethylation of its promoter region could potentially lead to the development of cancer. A follow-up study showed that hypomethylation and hypermethylation of genomic DNA was associated with arsenite exposure in vitro in human cells using a method sensitive to DNA methylation alterations Zhong and Mass, This suggests that the absolute level of genomic DNA methylation is less important than methylation within a specific DNA sequence.
Benbrahim-Tallaa et al. In some individuals chronically exposed to arsenic in drinking water, the p53 promoter region of DNA from whole blood shows a dose-dependent hypermethylation relative to control subjects Chanda et al. However, some of the arsenic-exposed individuals showed hypomethylation of this promoter region. In this same study, the tumor suppressor gene p16 was also hypermethylated in individuals exposed to high levels of arsenic.
The mechanism of the effect of arsenic on DNA methylation is not clear. Hypomethylation may be due to nutritional factors or inhibition of DNA methyltransferase. Also, S-adenosylmethionine, which is the methyl donor for the methylation of both DNA and arsenic in its metabolism, may potentially be shunted to the latter with increased exposure to arsenic. Pilsner et al. They observed that genomic PBL DNA methylation was positively associated with exposure to arsenic in a dose-dependent manner Pilsner et al.
In a group of arsenic-exposed individuals that developed skin lesions, it was found that folate deficiency, hyperhomocysteinemia, low urinary creatinine, and hypomethylation of PBL DNA were risk factors for the arsenic-induced skin lesions Pilsner et al.
Pilsner and colleagues suggested that the hypermethylation of PBL DNA that is associated with increased arsenic exposure might be an adaptive response because the hypomethylation of PBL DNA is associated with the risk for development of skin lesions. In addition, selenium may reduce the body of arsenic. Overall, the effect of arsenic on genomic DNA methylation is still not clear and requires further investigation.
The use of animals for the study of cancer causing agents has been a scientific foundation for many years. This is so that chemicals with unknown carcinogenicity in humans can be tested or that a potential mechanism can be studied for chemicals known to be carcinogenic. Leitch and Kennaway conducted some of the first animal carcinogenicity studies with arsenic.
Most of the animals died from the treatment, and no tumors were detected. In a second experiment, the arsenical solution was directly applied to mouse skin three times per week. About two-thirds of the initial animals died from the treatment, but a wart on one animal developed at the application site after 85 days of treatment.
This wart eventually developed into a metastasizing squamous cell epithelioma. A follow-up study under similar conditions produced negative results Leitch, These results by Leitch and Kennaway, of no carcinogenic effect with arsenic in one experiment, followed by a limited positive result, are similar to what has been published up to the s.
Many studies of experimental arsenic carcinogenesis using oral, dermal, or parenteral administration followed over the years. These studies included mice and rats Baroni et al. The results from these studies were largely negative or inconclusive. These carcinogenicity results as well as other findings up to this time led some to question the carcinogenic potency of arsenic in humans Frost, In the late s and early s, the potential for development of lung tumors in rats Ishinishi et al.
Epidemiological studies had shown that workers in the nonferrous metal smelting and arsenical pesticide manufacturing industries were at risk of developing lung cancer Lee and Franmeni, ; Ott et al. The experimental procedure was to instill arsenic arsenic trioxide, arsenic trisulfide, or calcium arsenate suspended in saline into the trachea of the animals. Animals received one dose per week for 15 weeks total dose, 3. The results for arsenic trisulfide were inconclusive. Calcium arsenate and arsenic trioxide were weakly tumorigenic.
The International Agency for Research on Cancer IARC, considers that these studies provided limited evidence for carcinogenicity of inorganic arsenicals. In the s, carcinogenicity studies in animals shifted from inorganic arsenic to its main mammalian metabolite, dimethylarsinic acid DMAs V.
Yamamoto et al. Rats were pretreated with five known carcinogens and then administered DMAs V in drinking water 50— ppm for 24 weeks. DMAs V promoted tumors in urinary bladder, kidney, liver, and thyroid gland. Urinary bladder showed the strongest response. This result was important because urinary bladder is one of the target organs for arsenic in humans NRC , Studies continued investigating the tumor promoting effects of DMAs V in rats and mice in urinary bladder and lung, respectively Yamanaka et al.
DMAs V in drinking water rats, 2— ppm; mice, — ppm promoted the tumorigenic effects of two initiators N-butyl-N- 4-hydroxybutyl nitrosamine and 4-nitroquinolone 1-oxide. Dose-dependent cellular proliferation of urinary bladder epithelium was observed in rats administered DMAs V in drinking water 10— ppm up to 23 weeks Wanibuchi et al. Studies then followed that assessed the complete carcinogenicity of DMAs V.
Wei et al. They observed dose-related development of bladder tumors. Tumors were not observed in other organs or in the control or Arnold et al. Although no treatment-related tumors were observed in mice, rats developed urinary bladder tumors. About chemeurope. Colorimetry-Software Day Free Trial. Your browser is not current. Microsoft Internet Explorer 6. Your browser does not support JavaScript.
To use all the functions on Chemie. DE please activate JavaScript. Isotopes of arsenic Although arsenic As has multiple isotopes , only one of these isotopes is stable; as such, it is considered a monoisotopic element. Table nuclide symbol Z p N n isotopic mass u half-life nuclear spin representative isotopic composition mole fraction range of natural variation mole fraction excitation energy 60 As.
Isotopes of germanium. The ionizing radiation that is emitted can include alpha particles alpha particles A form of particulate ionizing radiation made up of two neutrons and two protons. Alpha particles pose no direct or external radiation threat; however, they can pose a serious health threat if ingested or inhaled.
Some beta particles are capable of penetrating the skin and causing damage such as skin burns. Beta-emitters are most hazardous when they are inhaled or swallowed. Gamma rays can pass completely through the human body; as they pass through, they can cause damage to tissue and DNA. Radioactive decay occurs in unbalanced atoms called radionuclides. Elements in the periodic table can take on several forms. Some of these forms are stable; other forms are unstable.
Typically, the most stable form of an element is the most common in nature. However, all elements have an unstable form. Unstable forms emit ionizing radiation and are radioactive.
There are some elements with no stable form that are always radioactive, such as uranium. Elements that emit ionizing radiation are called radionuclides.
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