Dimethylarsinic Acid Concentrations Research Articles

Spatial distribution of arsenic and temporal variation of its concentration in rice

• In order to gain insights into the transport and distribution of arsenic (As) in intact rice (Oryza sativa) plants and its unloading into the rice grain, we investigated the spatial distribution of As and the temporal variation of As concentration in whole rice plants at different growth stages. To the best of our knowledge, this is the first time that such a study has been performed. • Inductively coupled plasma mass spectroscopy (ICP-MS) and high-performance liquid chromatography (HPLC)-ICP-MS were used to analyze total As concentration and speciation. Moreover, synchrotron-based X-ray fluorescence (SXRF) was used to investigate in situ As distribution in the leaf, internode, node and grain. • Total As concentrations of vegetative tissues increased during the 2 wk after flowering. The concentration of dimethylarsinic acid (DMA) in the caryopsis decreased progressively with its development, whereas inorganic As concentration remained stable. The ratios of As content between neighboring leaves or between neighboring internodes were c. 0.6. SXRF revealed As accumulation in the center of the caryopsis during its early development and then in the ovular vascular trace. • These results indicate that there are different controls on the unloading of inorganic As and DMA; the latter accumulated mainly in the caryopsis before flowering, whereas inorganic As was mainly transported into the caryopsis during grain filling. Moreover, nodes appeared to serve as a check-point in As distribution in rice shoots.

Effects of Water Management on Cadmium and Arsenic Accumulation and Dimethylarsinic Acid Concentrations in Japanese Rice

Rice consumption is a major source of cadmium and arsenic for the population of Asia. We investigated the effects of water management in rice paddy on levels of cadmium and arsenic in Japanese rice grains. Flooding increased arsenic concentrations in rice grains, whereas aerobic treatment increased the concentration of cadmium. Flooding for 3 weeks before and after heading was most effective in reducing grain cadmium concentrations, but this treatment increased the arsenic concentration considerably, whereas aerobic treatment during the same period was effective in reducing arsenic concentrations but increased the cadmium concentration markedly. Flooding treatment after heading was found to be more effective than flooding treatment before heading in reducing rice grain cadmium without a concomitant increase in total arsenic levels, although it increased inorganic arsenic levels. Concentrations of dimethylarsinic acid (DMA) in grain were very low under aerobic conditions but increased under flooded conditions. DMA accounted for 3-52% of the total arsenic concentration in grain grown in soil with a lower arsenic concentration and 10-80% in soil with a higher arsenic concentration. A possible explanation for the accumulation of DMA in rice grains is that DMA translocates from shoots/roots to the grains more readily than does inorganic arsenic.

Distribution and Speciation of Arsenic by Transplacental and Early Life Exposure to Inorganic Arsenic in Offspring Rats

The amount of arsenic compounds was determined in the liver and brain of pups and in breast milk in the pup's stomach in relation to the route of exposure: transplacental, breast milk, or drinking water. Forty-eight pregnant rats were randomly divided into four groups, each group was given free access to drinking water that contained 0, 10, 50, and 100 mg/L NaAsO(2) from gestation day 6 (GD 6) until postnatal day 42 (PND 42). Once pups were weaned, they started to drink the same arsenic-containing water as the dams. Contents of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and trimethylarsenic acid (TMA) in livers and brains of the pups on PND 0, 15, 28, and 42 and breast milk taken from the pup's stomach on PND 0 and 15 were detected using the hydride generation atomic absorption spectroscopy method. Concentrations of iAs, MMA, and DMA in the breast milk, the brain, and the liver of the pups increased with the concentration of arsenic in drinking water on PND 0, 15, 28, and 42. Compared to the liver or brain, breast milk had the lowest arsenic concentrations. There was a significant decrease in the levels of arsenic species on PND 15 compared to PND 0, 28, or 42. It was confirmed that arsenic species can pass through the placental barrier from dams to offspring and across the blood-brain barrier in the pups, and breast milk from dams exposed to arsenic in drinking water contains less arsenic than the liver and brain of pups.

Seasonal dynamics of biodegradation activities for dimethylarsinic acid (DMA) in Lake Kahokugata

The microbial activities in aquatic environments significantly influence arsenic cycles such as the turnover between inorganic arsenic and organoarsenic compounds. In Lake Kahokugata, inorganic arsenic was detected at concentrations ranging from 2.8 to 23 nM in all seasons, while the concentrations of dimethylarsinic acid (DMA) produced by microorganisms such as phytoplankton changed seasonally and showed a peak in winter. The changes in the concentrations of methylarsenic species did not correlate with the changes in phytoplankton abundance (chlorophyll a contents), suggesting that DMA-degradation is related to this inconsistency. DMA (1 μM) added into the lake water was converted to inorganic arsenic at 20 °C only under anaerobic and dark conditions, while DMA degradation was diminished under aerobic or light conditions. Moreover, DMA added to the lake water samples collected through four seasons was degraded at the same rates under anaerobic and dark conditions at 20 °C. However, at 30 °C, 1 μM of DMA in the summer lake water samples was rapidly degraded in 7 and 21 d. In contrast, DMA degradation was diminished in the winter lake water samples at 4 °C of incubation. Presumably, DMA-biodegradation activities are mainly controlled by changes in the water temperature in Lake Kahokugata, where the arsenic concentrations change seasonally.

Mitigation of Arsenic Accumulation in Rice with Water Management and Silicon Fertilization

Rice represents a major route of As exposure in populations that depend on a rice diet. Practical measures are needed to mitigate the problem of excessive As accumulation in paddy rice. Two potential mitigation methods, management of the water regime and Si fertilization, were investigated under greenhouse conditions. Growing rice aerobically during the entire rice growth duration resulted in the leastAs accumulation. Maintaining aerobic conditions during either vegetative or reproductive stage of rice growth also decreased As accumulation in rice straw and grain significantly compared with rice grown under flooded conditions. The effect of water management regimes was consistent with the observed effect of flooding-induced arsenite mobilization in the soil solution. Aerobic treatments increased the percentage of inorganic As in grain, but the concentrations of inorganic As remained lower than in the flooded rice. Silicon fertilization decreased the total As concentration in straw and grain by 78 and 16%, respectively, even though Si addition increased As concentration in the soil solution. Silicon also significantly influenced As speciation in rice grain and husk by enhancing methylation. Silicon decreased the inorganic As concentration in grain by 59% while increasing the concentration of dimethylarsinic acid (DMA) by 33%. There were also significant differences between two rice genotypes in grain As speciation. This study demonstrated that water management Si fertilization, and selection of rice cultivars are effective measures that can be used to reduce As accumulation in rice.

Biological and Microcalorimetric Studies of the Toxic Effect of Organoarsenic(V) Compounds to Wild Strain of Bacillus thuringiensis

Microcalorimetric and biological methods were carried out to determine the toxicity of dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) to wild strain of Bacillus thuringiensis. Thermokinetic parameters were obtained from the power-time curves, showing that the peak-heat output power, total heat output, and number of colonies decreased with the increases in concentration of DMA and MMA. In addition, the generation time and peak maximal time increased with the increases in the dosage of DMA and MMA. The half inhibitory concentrations of DMA and MMA were 99.02 and 142.02 microg mL(-1), respectively for the wild strain of B. thuringiensis. DMA shows higher toxicity to bacteria than MMA. The toxicity resistance of B. thuringiensis against organoarsenic(V) is quite high for the wild strain. Our work demonstrates that microcalorimetry is a very sensitive, simple, and useful technique for in vitro investigation of the toxic effect of organoarsenic(V) on microbial activity.

8-Hydroxy-2′-deoxyguanosine (8-OHdG) as a possible marker of arsenic poisoning: a clinical case study on the relationship between concentrations of 8-OHdG and each arsenic compound in urine of an acute promyelocytic leukemia patient being treated with arsenic trioxide

Arsenic trioxide (ATO) is an effective therapeutic agent for acute promyelocytic leukemia (APL). In the present study, the concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and arsenic compounds [(dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), As(V), and As(III)] in urine of an APL patient were determined during ATO treatment. The concentrations of 8-OHdG, DMA, and MMA were increased, especially during the fi rst consolidation therapy. Signifi cant positive correlations were observed between concentrations of 8-OHdG and DMA, between concentrations of 8-OHdG and MMA, and between concentrations of 8-OHdG and the sum of arsenic compounds. The present study supports the idea that urinary 8-OHdG can be a marker for arsenic poisoning, when it is detected together with DMA and MMA. In addition, this study is the fi rst to show the relationship between 8-OHdG and levels of arsenic compounds in urine of an APL patient being treated with ATO.

Effect of eutrophication on the distribution of arsenic species in eutrophic and mesotrophic lakes

Effects of eutrophication on arsenic speciation were studied in eutrophic Lake Kiba and mesotrophic Lake Biwa, Japan. By combining hydride generation atomic absorption spectrometry with ultraviolet irradiation, inorganic, methyl and ultraviolet-labile fractions of arsenic were determined. In both Lakes, inorganic species (As(V + III)) dominated over other forms of arsenic all the year round. Most of methylarsenic fraction was dimethylarsinic acid (DMAA), and the concentration of monomethylarsonic acid (MMAA) was below the detection limit. Measurements of size-fractioned arsenic concentrations in water column indicate that most of the DMAA was distributed in truly dissolved fraction (< 10 kDa), while ultraviolet-labile fractions were distributed in particulate (> 0.45 µm) and colloidal (10 kDa–0.45 µm) fractions. Arsenic speciation in eutrophic Lake Kiba fluctuated greatly with season. The ultraviolet-labile fractions were observed with the increase of DMAA from May to October, and they disappeared with the decrease of DMAA in January. In mesotrophic Lake Biwa, the ultraviolet-labile fractions of arsenic were not influenced as much as those in eutrophic Lake Kiba. On the other hand DMAA concentration was higher in Lake Biwa compared to that in Lake Kiba. The results suggest that the biosynthesis of complex organoarsenicals was enhanced by eutrophication, and the arsenic speciation would be influenced by the balance of biological processes in natural waters.

Urinary Arsenic Speciation and its Correlation with 8-OHdG in Chinese Residents Exposed to Arsenic Through Coal Burning

In contrast to arsenicosis caused by consumption of water contaminated by naturally occurring inorganic arsenic, human exposure to this metalloid through coal burning has been rarely reported. In this study, arsenic speciation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in urine were determined in the Chinese residents exposed to arsenic through coal burning in Guizhou, China, an epidemic area of chronic arsenic poisoning caused by coal burning. The urinary concentrations of inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and total arsenic (tAs) of high-arsenic exposed subjects were significantly higher than those of low-arsenic exposed residents. A biomarker of oxidative DNA damage, urinary 8-OHdG level was significantly higher in high-arsenic exposed subjects than that of low exposed. Significant positive correlations were found between 8-OHdG levels and concentrations of iAs, MMA, DMA and tAs, respectively. In addition, a significant negative correlation was observed between 8-OHdG levels and the secondary methylation ratio (DMA/(MMA + DMA)). The results suggest that chronic arsenic exposure through burning coal rich in arsenic is associated with oxidative DNA damages, and that secondary methylation capacity is potentially related to the susceptibility of individuals to oxidative DNA damage induced by arsenic exposure through coal burning in domestic living.

Controlling the Fate of Roxarsone and Inorganic Arsenic in Poultry Litter

A growing body of literature reports 3-nitro-4-hydroxyphenylarsonic acid (roxarsone) degradation in poultry litter (PL) to the more toxic inorganic arsenic (As). Aluminum-based drinking-water treatment residuals (WTR) present a low-cost amendment technology to reduce As availability in PL, similar to the use of alum to reduce phosphorus availability. Batch experiments investigated the effectiveness of WTR in removing roxarsone and inorganic As species from PL aqueous suspensions. Incubation experiments with WTR-amended PL evaluated the effects of WTR application rates (2.5-15% by weight) and incubation time (up to 32 d) at two incubation temperatures (23 and 35 degrees C) on As availability in PL. Batch PL aqueous experiments showed the high affinity of As(V), As(III), dimethylarsinic acid (DMA), monomethylarsonic acid (MMA), and roxarsone for the WTR. The 10% WTR amendment rate decreased As availability in PL by half of that of the unamended (no WTR) PL-incubated samples. The reduction in dissolved As concentrations during incubation of WTR-amended PL samples was kinetically limited, being complete within 13 d. Parallel reductions in roxarsone, As(V), and DMA concentrations were observed with liquid chromatography-inductively coupled plasma mass spectrometry, whereas As(III) and MMA concentrations were always <5% of dissolved As. Incubation temperature did not significantly (p > 0.05) influence dissolved As concentrations in the WTR-amended PL. Potential formation of a copper-containing roxarsone metabolite was considered in PL aqueous suspensions with the aid of electrospray mass spectrometry. Further experiments in the field are necessary to ensure that sorbed As is stable in WTR-amended PL.

Influence of phosphate and iron ions in selective uptake of arsenic species by water fern (Salvinia natans L.)

Abstract In the present study, the effect of phosphate ion and iron hydroxides (Fe-plaques) on the selective uptake of arsenic species by water fern (Salvinia natans L.) was investigated. The plants were grown for 5 days in aqueous Murashige and Skoog (MS) culture media modified in arsenic and phosphate concentrations. Arsenic accumulations in S. natans L. increased with the increase of arsenate and DMAA concentrations in the culture solutions. Compared to the control treatment, S. natans L. accumulated significantly higher amount of arsenic from phosphate-deficient solutions, when the source was arsenate. However, arsenic uptake was not affected significantly by phosphate, when the source was dimethylarsinic acid (DMAA). From solutions containing 100 μM of phosphate and 4.0 μM of either arsenate or DMAA, the S. natans L. accumulated 0.14 ± 0.02 and 0.02 ± 0.00 μmol (g dry weight)−1 of arsenic, respectively. In contrast, plants accumulated 0.24 ± 0.06 and 0.03 ± 0.00 μmol (g dry weight)−1 of arsenic from solutions containing 4.0 μM of either arsenate and DMAA in phosphate deficient conditions, respectively. Thus, it is reasonable to state that increasing phosphate concentration in culture solutions decreased the arsenic uptake into the water fern significantly, when the source was arsenate. Moreover, arsenic and phosphate content in plant tissue correlated significantly (r = −0.66; p 0.05). Similarly, significant correlation was observed between arsenic and iron content in plant tissues (r = 0.66; p

Organic arsenic removal from an aqueous solution by iron oxide-coated fungal biomass: An analysis of factors influencing adsorption

Abstract A two-level seven-factor (2 7-2 ) fractional factorial design analysis was conducted to examine the parameters influencing dimethylarsinic acid (DMA) removal from an aqueous solution using iron oxide-coated A. niger biomass. The factors examined were the concentration of DMA in solution, the mass of the adsorbent, the solution temperature, the Ca 2+ ions in solution, the Fe 2+ ions in solution, the SO 4 2− ions in solution, and the Cl − ions in solution. The magnitude of the influence of the factors considered on DMA removal was observed in the order: presence of Ca 2+ ions in solution > the DMA concentration > solution temperature > presence of SO 4 2− in solution > presence of Fe 2+ in solution > the mass of adsorbent > the presence of Cl − in solution.

Variation of Total and Speciated Arsenic in Commonly Consumed Fish and Seafood

ABSTRACT This article compiles available data and presents an approach for predicting human intakes of inorganic arsenic (Asi), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) from marine, estuarine, and freshwater seafood when only total arsenic (Astot) concentrations are reported. Twenty studies provided data on total arsenic (Astot) and Asi. Mean Asi concentrations were approximately 10 to 20 ng/g wet weight (ww) in freshwater, anadromous, and marine fish, whereas crustaceans and molluscs had mean Asi concentrations of 40 to 50 ng/g ww. Thirteen studies provided data for MMA and DMA. MMA was seldom detected, whereas DMA averaged 10 ng/g ww in freshwater fish, and 45 to 95 ng/g ww in anadromous fish, marine fish, crustaceans, and molluscs. There was little correlation between Astot concentrations and Asi concentrations; however, when only Astot data are available to assess health risks from arsenic in seafood, these data could support conservative, upper end estimates of the percent of Astot likely to be Asi. For marine and estuarine fish, and crustaceans and molluscs 2–3% of Astot was Asi at the 75th percentile of the dataset. For freshwater fish Asi was 10% of Astot at the 75th percentile. Due to the nonlinearity and low carcinogenic potency of DMA, the reported DMA concentrations should not contribute substantially to potential health risks from arsenic in seafood.

HPLC‐ICP‐MS Speciation Analysis of Arsenic in Urine of Japanese Subjects without Occupational Exposure

The toxicity and carcinogenicity of arsenic depend on its species. Individuals living in Japan consume much seafood that contains high levels of organoarsenics. Speciation analysis of urinary arsenic is required to clarify the health risks of arsenic intake. There has been no report of urinary arsenic analysis in Japan using high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). We performed speciation analysis of urinary arsenic for 210 Japanese male subjects without occupational exposure using HPLC-ICP-MS. The median values of urinary arsenics were as follows: sodium arsenite (AsIII), 3.5; sodium arsenate (AsV), 0.1; monomethylarsonic acid (MMA), 3.1; dimethylarsinic acid (DMA), 42.6; arsenobetaine (AsBe), 61.3; arsenocholine, trimethylarsine oxide, and unidentified arsenics (others), 5.2; and total arsenic (total As), 141.3 microgAs/l. The median creatinine-adjusted values were as follows: AsIII, 3.0; AsV, 0.1; MMA, 2.6; DMA, 35.9; AsBe, 52.1; others 3.5; and total As, 114.9 microgAs/g creatinine. Our findings indicate that DMA and AsBe levels in Japan are much higher than those found in Italian and American studies. It appears that the high levels of DMA and AsBe observed in Japan may be due in part to seafood intake. ACGIH and DFG set the BEI and BAT values for occupational arsenic exposure as 35 microgAs/l and 50 microgAs/l, respectively, using the sum of inorganic arsenic (iAs), MMA, and DMA. In the general Japanese population, the sums of these were above 50 microgAs/l in 115 (55%) samples. We therefore recommend excluding DMA concentration in monitoring of iAs exposure.

Response of Pepper Plants (Capsicum annum L.) on Soil Amendment by Inorganic and Organic Compounds of Arsenic

The influence of soil contamination by inorganic and organic arsenic compounds on uptake, accumulation, and transformation of arsenic in pepper (Capsicum annum L.) was investigated in greenhouse pot experiments under controlled conditions. Pepper plants were cultivated in substrate amended by aqueous solutions of arsenite, arsenate, methylarsonic acid (MA), and dimethylarsinic acid (DMA) applied individually into cultivation substrate at concentrations of 15 mg As per kg of substrate. The plant availability of the arsenicals increased in the order arsenite = arsenate < MA < DMA. The highest arsenic concentrations were found in roots followed by stems, leaves, and fruits regardless of arsenic compound applied. In the control samples of pepper fruits, As(III), As(V), and DMA were present (25%, 37%, and 39% of the water-extractable arsenic). In control stems + leaves and roots, As(V) was the major compound (63% and 53% in a phosphate buffer extract) followed by As(III) representing 33% and 42%. Additionally, low concentrations (not exceeding 5%) of DMA and MA were detected as well. In all the soils analyzed after the first harvest of pepper fruits, arsenate was the dominating compound followed by arsenite. Methylarsonic acid, methylarsonous acid, and DMA were present at varying concentrations depending on the individual soil treatments. In the treated plants, the arsenic compounds in plant tissues reflected predominantly the extractable portions of arsenic compounds present in soil after amendment, and this pattern was more significant in the first part of vegetation period. The results confirmed the ability of generative parts of plants to accumulate preferably organic arsenic compounds, whereas in the roots and aboveground biomass, mainly inorganic arsenic species are present. Evidently, the source of soil arsenic contamination affects significantly the extractable portions of arsenic compounds in soil and subsequently the distribution of arsenic compounds within the plants.

Quantitation of Toxic Arsenic Species and Arsenobetaine in Pacific Oysters Using an Off-line Process with Hydride Generation−Atomic Absorption Spectroscopy

An off-line process-based speciation technique was devised here to quantitatively determine toxic inorganic arsenic (iAs), methylarsonic acid (MA), dimethylarsinic acid (DMA), and the dominant, albeit virtually nontoxic, arsenobetaine (AB) in Pacific oysters (Crassostrea gigas). Oysters were extracted with fresh methanol-water (8+2), and this was replicated three times. They were then evaporated to near dryness and subsequently redissolved in pure water; defatting was then performed with a C18 cartridge. The trace hydride active arsenic species, that is, iAs, MA, and DMA, in the defatted solutions were determined with a sensitive hydride generation-packed coldfinger trap-atomic absorption spectrometric (HG-PCFT-AAS) coupled system. The arsenicals that were desorbed from the cation-exchange resin (Dowex 50W-X8) in the washings of 4 M NH3 were categorized on the basis of AB + DMA. The total quantity of arsenic in the recovered AB + DMA was determined with a commercial hydride generation-atomic absorption spectrometric (HG-AAS) system, and finally, AB was calculated from (AB + DMA) - DMA. The average concentrations of iAs, MA, DMA, AB, and total arsenic (TAs) in the oysters collected from six aquacultural sites along the west coast of Taiwan were, respectively, 0.15, 0.06, 0.64, 6.93, and 13.74 mg kg(-1) of dry weight. AB was the major species, whereas iAs (arsenite + arsenate) were the most toxic species, although the iAs made up only approximately 1% of the TAs in the oysters. The lifetime target cancer risk, as determined by the concentration of iAs on a fresh weight basis in the oysters, was well below the ordinary health protection criteria (10(-6)).

Tissue distribution of arsenic species in rabbits after single and multiple parenteral administration of arsenic trioxide: tissue accumulation and the reversibility after washout are tissue-selective.

Parenteral administration of arsenic trioxide has recently been recognized as an effective antineoplastic therapy, especially for the treatment of acute promyelocytic leukemia. Its efficacy and toxicity are concentration-dependent and are related to the fractions of different arsenic species and the degree of methylation. In this study, arsenic trioxide was given parenterally to rabbits as a single dose or as a daily dose (0.2, 0.6, and 1.5 mg/kg) for 30 days. The blood and organ concentrations of the arsenic species, including As(III), dimethylarsinic acid (DMA), and monomethylarsonic acid (MMA), were studied on day 1 (single-dose study), day 30 (multiple dosing study), and day 60 (reversibility study). As(III) was the major detectable arsenic species in the blood. The pharmacokinetic parameters (total clearance, area under the curve, etc.) for As(III) indicated a limit for the capacity to eliminate As(III) at the dose of 1.5 mg/kg, and were quite the same after a single dose or chronic multiple dosing. In tissues, DMA was found to be the major metabolite and the concentrations of DMA, As(III), and MMA in general increased with the dose, with the increase most significant at a dose of 1.5 mg/kg. However, normalized tissue distribution of As(III) in the kidney on day 1, but not on day 30, was nonlinear. Along with decreased levels of As(III) and increased levels of DMA, an inducible capacity for methylating As(III) to DMA after chronic dosing in kidney was suggested. The tissue concentration of DMA was highest in lung and liver, and the normalized tissue distributions in liver on day 30 were nonlinear, suggesting a limit in eliminating DMA after a chronic high load of As(III). Tissue concentrations of As(III), DMA, and MMA in bladder increased dramatically after chronic dosing. However, after washout for 30 days, As(III), DMA, and MMA were all undetectable in bladder and liver. However, As(III) in hair and low levels of DMA in lung, kidney, heart and hair were still detected. In conclusion, in rabbits we found a similar pharmacological profile after a single dose or chronic multiple dosing of parenteral arsenic trioxide, with a limiting metabolizing capacity at a dose of 1.5 mg/kg. Tissue accumulation of arsenic species, mainly DMA, and its reversibility after washout were tissue-selective. The potential for late toxicities of arsenic trioxide in organs with a significant tendency for arsenic accumulation with low reversibility should be closely monitored.

Metallothionein (I/II) suppresses genotoxicity caused by dimethylarsinic acid

Arsenic is an environmental chemical of considerable concern due to its association with an increased risk of human cancer. Dimethylarsinic acid (DMAA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To better clarify the role of metallothionein (MT) in modifying DMAA genotoxicity, MT-I/II null mice, and the corresponding wild-type mice, were exposed to DMAA (0, 188, 375 or 750 mg/kg body weight) via a single oral dose. Twenty-four hours after the DMAA injection, there was increased formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in serum and urine and a higher number of DNA strand breaks in peripheral blood cells. These increased levels were concomitant with increasing dose concentrations of DMAA in both strains of mice and they were significantly higher in MT-I/II null mice than in wild-type mice. Furthermore, the induction of apoptotic cells in the urinary bladder epithelium of MT-I/II null mice was significantly higher than in dose-matched wild-type mice exposed to DMAA. On the other hand, in both liver and in the alveolar and bronchial areas of the lung, the extent of DMAA-induced apoptosis was not different between wild-type and MT-I/II null mice and was increased in both strains. In addition, the concentration of hepatic MT in wild-type mice increased in a DMAA dose-dependent manner but was undetectable in MT-I/II null mice and could not subsequently be induced by DMAA. In conclusion, DMAA exposure causes oxidative stress, DNA damage and specific induction of apoptosis in target organs of arsenic carcinogenesis, which may be attributable to the mechanism(s) of arsenic-induced carcinogenesis in rodents. MT exhibited some protective roles during DNA damage presumably by acting as an antioxidant.

Arsenic uptake and arsenic compounds in cultivated Agaricus bisporus

In view of recent findings that most wild-growing mushrooms contain mainly organo-arsenic compounds, this work was conducted as a preliminary study of arsenic uptake and the distribution of arsenic compounds in mushrooms grown under controlled conditions with the intention of assessing potential health risks involved in the consumption of cultivated Agaricus bisporus. Agaricus bisporus was grown on substrate containing 1000 mg As kg −1 As(V) as well as on control substrate without arsenic addition. Agaricus bisporus grown on the control substrate (3.8 ± 0.2 μg As/g dry mass) contained 0.50 ± 0.03 μg As/g dry mass, whereas 22.8 ± 1.0 μg As/g dry mass were found in the mushrooms grown on the substrate amended with As(V). Arsenic speciation analysis of extracts of the mushrooms revealed that the main proportion of the incorporated arsenic in the treated Agaricus bisporus was present as inorganic arsenic. In the treated mushrooms the concentration of dimethylarsinic acid was twice as high as in the control mushrooms and the concentration of methylarsonic acid was almost 4 times higher than the concentration in the control mushrooms. Surprisingly, the concentration of arsenobetaine in the treated mushrooms was approximately half the concentration in the control sample.

Pharmacokinetics (PK) of arsenic trioxide in cancer patients (pts) with renal dysfunction: Preliminary results

2018 Background: Trisenox (arsenic trioxide- ATO) is approved for treatment of relapsed/refractory acute promyelocytic leukemia. This study was designed to determine the PK of ATO in adult cancer pts with renal dysfunction and to evaluate its safety. Methods: 14 pts (median age 66 yrs, 29–85) in 4 renal function (RF) groups (normal- CLCR >80 mL/min; mild dysfunction: 50–80; moderate: 30–49; severe: <30) received IV ATO 0.15 mg/kg/d twice weekly for 4 wks, followed by 2 weeks without drug. Pts were treated for 2 six-week cycles. Arsenious acid (AsIII), arsenic acid (AsV), monomethyl arsonic acid (MMA), and dimethylarsinic acid (DMA) concentrations in plasma and urine were determined by validated methods based on anion exchange HPLC combined with ICPMS. Results: AsIII was rapidly distributed throughout the body (Table). MMA and DMA concentrations reached maximum values 24 hr after ATO. Urinary excretion of all As-containing species accounted for 27% of the dose (days 1–3). No significant correlations were found between AsIII PK parameters and RF, expressed by the CLCR value, except for urinary excretion, which was linearly correlated with CLCR (p<0.01). Exposure to inactive metabolites MMA and DMA inversely correlated with RF (p<0.05). After repeated dosing, plasma concentrations and excretion of methylated metabolites in urine were greater than those observed after the 1st administration, suggesting accumulation. The only severe drug-related toxicity was 1 grade 3 hyperglycemia. Conclusions: Renal excretion does not appear to be the main elimination route for AsIII, which is extensively metabolized to MMA and DMA. Systemic exposure of patients to AsIII, the active species, appears unaffected by RF, even in pts with severe dysfunction. Some accumulation of slowly eliminated metabolites MMA and DMA occurs on repeated dosing. ATO is well-tolerated at this dose in this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc. Cell Therapeutics, Inc.