A comparative study on acute toxicity of methylarsonic acid, dimethylarsinic acid and trimethylarsine oxide in mice

Kaise, Toshikazu; Yamauchi, Hiroshi; Horiguchi, Yoshiya; Tani, Takao; Watanabe, Shun-ichi; Hirayama, Teruhisa; Fukui, Shozo

doi:10.1002/aoc.590030311

Cited by 79 publications

(47 citation statements)

References 13 publications

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“…The oral LD50s of MMA(V) and its sodium salts are 1.8 g/ kg in mice (Kaise et al, 1989) and >800 mg/kg (Gaines and Linder, 1986) in rats. The reproductive capacity of male mice repeatedly administered the monosodium salt of MMA(V) (MSMA) (11.9 and 119 mg/kg) over several weeks was reduced (Prukop and Savage, 1986).…”

Section: Introductionmentioning

confidence: 99%

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

Hughes

Devesa

Adair

et al. 2005

Toxicology and Applied Pharmacology

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Exposure to monomethylarsonic acid (MMA(V)) and monomethylarsonous acid (MMA(III)) can result from their formation as metabolites of inorganic arsenic and by the use of the sodium salts of MMA(V) as herbicides. This study compared the disposition of MMA(V) and MMA(III) in adult female B6C3F1 mice. Mice were gavaged po with MMA(V), either unlabeled or labeled with 14 C at two dose levels (0.4 or 40 mg As/kg). Other mice were dosed po with unlabeled MMA(III) at one dose level (0.4 mg As/kg). Mice were housed in metabolism cages for collection of excreta and sacrificed serially over 24 h for collection of tissues. MMA(V)-derived radioactivity was rapidly absorbed, distributed and excreted. By 8 h post-exposure, 80% of both doses of MMA(V) were eliminated in urine and feces. Absorption of MMA(V) was dose dependent; that is, there was less than a 100-fold difference between the two dose levels in the area under the curves for the concentration-time profiles of arsenic in blood and major organs. In addition, urinary excretion of MMA(V)-derived radioactivity in the low dose group was significantly greater (P < 0.05) than in the high dose group. Conversely, fecal excretion of MMA(V)-derived radioactivity was significantly greater (P < 0.05) in the high dose group than in the low dose group. Speciation of arsenic by hydride generation-atomic absorption spectrometry in urine and tissues of mice administered MMA(V) or MMA(III) found that methylation of MMA(V) was limited while the methylation of MMA(III) was extensive. Less than 10% of the dose excreted in urine of MMA(V)-treated mice was in the form of methylated products, whereas it was greater than 90% for MMA(III)-treated mice. In MMA(V)-treated mice, 25% or less of the tissue arsenic was in the form of dimethylarsenic, whereas in MMA (III)-treated mice, 75% or more of the tissue arsenic was in the form of dimethylarsenic. Based on urinary analysis, administered dose of MMA(V) did not affect the level of its metabolites excreted. In the tested range, dose affects the absorption, distribution and route of excretion of MMA(V) but not its metabolism.

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Section: Introductionmentioning

confidence: 99%

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

Hughes

Devesa

Adair

et al. 2005

Toxicology and Applied Pharmacology

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“…Methylation of inorganic arsenic to form both DMA and methylarsonic acid (MMA) has traditionally been viewed as a mechanism to facilitate the detoxification and excretion of arsenic. This is principally because DMA, in particular, is over 10-fold less acutely toxic than inorganic arsenic (Kaise et al, 1985(Kaise et al, , 1989. However, evidence suggesting that DMA itself has unique toxic properties has accumulated in the * Corresponding author.…”

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confidence: 99%

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

2001

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Dimethylarsinic acid (DMA) has been used as a herbicide (cacodylic acid) and is the major metabolite formed after exposure to tri-(arsenite) or pentavalent (arsenate) inorganic arsenic (iAs) via ingestion or inhalation in both humans and rodents. Once viewed simply as a detoxification product of iAs, evidence has accumulated in recent years indicating that DMA itself has unique toxic properties. DMA induces an organ-specific lesion -single strand breaks in DNA -in the lungs of both mice and rats and in human lung cells in vitro. Mechanistic studies have suggested that this damage is due mainly to the peroxyl radical of DMA and production of active oxygen species by pulmonary tissues. Multi-organ initiation-promotion studies have demonstrated that DMA acts as a promotor of urinary bladder, kidney, liver and thyroid gland cancers in rats and as a promotor of lung tumors in mice. Lifetime exposure to DMA in diet or drinking water also causes a dose-dependent increase in urinary bladder tumors in rats, indicating that DMA is a complete carcinogen. These data collectively suggest that DMA plays a role in the carcinogenesis of inorganic arsenic. Published by Elsevier Science Ireland Ltd.Keywords: Arsenic; Cancer; Dimethylarsinic acid www.elsevier.com/locate/toxicol Dimethylarsinic acid 1 (DMA; see Fig. 1) has been used as a herbicide and is also the major metabolite formed after exposure to trivalent (arsenite, AsIII) or pentavalent (arsenate, AsV) inorganic arsenic via ingestion or inhalation in both humans and most rodents (US EPA, 1975; ATSDR, 1993). Methylation of inorganic arsenic to form both DMA and methylarsonic acid (MMA) has traditionally been viewed as a mechanism to facilitate the detoxification and excretion of arsenic. This is principally because DMA, in particular, is over 10-fold less acutely toxic than inorganic arsenic (Kaise et al., 1985(Kaise et al., , 1989. However, evidence suggesting that DMA itself has unique toxic properties has accumulated in the * Corresponding author. Tel.: +1-919-5410043; fax: +1-919-5415394.E-mail address: kenyon.elaina@epa.gov (E.M. Kenyon). 1 Unless specifically stated otherwise, the abbreviation DMA refers to pentavalent dimethyl form of arsenic. The distinction is important because emerging evidence suggests that both trivalent monomethylated arsenic and trivalent DMA are more tissue-reactive and cytotoxic than their pentavalent counterparts.0300-483X/01/$ -see front matter Published by Elsevier Science Ireland Ltd. PII: S 0 3 0 0 -4 8 3 X ( 0 0 ) 0 0 4 5 8 -3

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“…The methylation of inorganic arsenicals was initially thought to be a detoxification process because the toxicity of MMAs V and DMAs V is substantially lower than that of inorganic arsenicals. 7,8) However, it was recently reported that toxic MMAs III and DMAs III might be produced through the methylation of inorganic arsenicals, 9,10) and that arsenical-glutathione conjugates, such as MMAs III DG and DMAs III G, might be generated in vivo. [12][13][14] 1830 Vol.…”

Section: Discussionmentioning

confidence: 99%

“…5,6) It is believed that methylation of inorganic arsenicals results in a reduction in general toxicity, as indicated by their increased in vivo lethal dose in 50% of a population (LD 50 ) and in vitro lethal concentration in 50% of a population (LC 50 ). 7,8) However, recent studies have increasingly suggested that the methylation of inorganic arsenicals is not a universal detoxification mechanism. Some researchers have reported that trivalent methyl arsenicals, such as monomethylarsonous acid (MMAs III ) and dimethylarsinous acid (DMAs III ), were found in urine collected from people who had been exposed to high concentrations of inorganic arsenicals, 9,10) and that synthetic trivalent methyl arsenicals, such as monomethylarsine oxide (MMAs III O) and iododimethylarsine (DMAs III I), are more cytotoxic in vitro than inorganic arsenicals and pentavalent methyl arsenicals.…”

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confidence: 99%

Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds

Kojima

Sakurai

Waalkes

et al. 2005

Biological & Pharmaceutical Bulletin

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Arsenic is a metalloid element that is widely distributed in the environment as a natural component of soil and in water as inorganic trivalent (arsenite) or pentavalent (arsenate) forms, 1) and its toxicity has been known since ancient times. In Asia and the Americas, chronic arsenic poisoning has occurred as a result of the consumption of high levels of arsenic-contaminated well water. Epidemiological studies have provided clear evidence that inorganic arsenicals are a human carcinogen with target sites including liver, skin, lung, kidney and urinary bladder.2) However, the mechanism of arsenic-induced impediment is not clear. On the other hand, inorganic arsenite has emerged as a potent chemotherapeutic agent with remarkable efficacy for certain human cancers, such as acute promyelocytic leukemia.3,4) It would thus appear that environmental and iatrogenic exposure to arsenic will continue to be common.In humans and numerous experimental animals, pentavalent arsenate is rapidly reduced to trivalent arsenite. 5) Subsequently, it is enzymatically methylated into organic arsenicals, such as monomethylarsonic acid (MMAs V ) and dimethylarsinic acid (DMAs V ).6) MMAs V and DMAs V are the major organic pentavalent arsenic metabolites in human urine after exposure to inorganic arsenicals. 5,6) It is believed that methylation of inorganic arsenicals results in a reduction in general toxicity, as indicated by their increased in vivo lethal dose in 50% of a population (LD 50 ) and in vitro lethal concentration in 50% of a population (LC 50 ). 7,8) However, recent studies have increasingly suggested that the methylation of inorganic arsenicals is not a universal detoxification mechanism. Some researchers have reported that trivalent methyl arsenicals, such as monomethylarsonous acid (MMAs III ) and dimethylarsinous acid (DMAs III ), were found in urine collected from people who had been exposed to high concentrations of inorganic arsenicals, 9,10) and that synthetic trivalent methyl arsenicals, such as monomethylarsine oxide (MMAs III O) and iododimethylarsine (DMAs III I), are more cytotoxic in vitro than inorganic arsenicals and pentavalent methyl arsenicals.11) Trivalent methyl arsenicals are thought to be generated as arsenical-glutathione conjugates, such as mono-methylarsonous diglutathione (MMAs III DG) and dimethylarsinous glutathione (DMAs III G), in the human body. [12][13][14] It was also reported that reduced glutathione (GSH) nonenzymatically reduces pentavalent methyl arsenicals to trivalent methyl arsenicals in water, thus resulting in the formation of MMAs III DG and DMAs III G in vitro.

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A comparative study on acute toxicity of methylarsonic acid, dimethylarsinic acid and trimethylarsine oxide in mice

Cited by 79 publications

References 13 publications

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

Cytolethality of Glutathione Conjugates with Monomethylarsenic or Dimethylarsenic Compounds

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