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PubMed2006

Arsenic exposure from drinking water and risk of premalignant skin lesions in Bangladesh: baseline results from the Health Effects of Arsenic Longitudinal Study.

Millions of persons around the world are exposed to low doses of arsenic through drinking water. However, estimates of health effects associated with low-dose arsenic exposure have been extrapolated from high-dose studies. In Bangladesh, many persons have been exposed to a wide range of doses of arsenic from drinking water over a significant period of time. The authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002 for the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for all arsenic exposure measures. Compared with drinking water containing <8.1 microg/liter of arsenic, drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 microg/liter of arsenic was associated with adjusted prevalence odds ratios of skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. These findings provide information that should be considered in future research and policy decisions.

Adult↗
PubMed2004

Animal models for arsenic carcinogenesis: inorganic arsenic is a transplacental carcinogen in mice.

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.

Animals↗
PubMed2004

Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethylation: implications for arsenic hepatocarcinogenesis.

Inorganic arsenic is a human carcinogen that can target the liver, but its carcinogenic mechanisms are still unknown. Global DNA hypomethylation occurs during arsenic-induced malignant transformation in rodent liver cells. DNA hypomethylation can increase gene expression, particularly when occurring in the promoter region CpG sites, and may be a non-genotoxic mechanism of carcinogenesis. Thus, in the present study liver samples of male mice exposed to 0 (control) or 45 p.p.m. arsenic (as NaAsO(2)) in the drinking water for 48 weeks were analyzed for gene expression and DNA methylation. Chronic arsenic exposure caused hepatic steatosis, a lesion also linked to consumption of methyl-deficient diets. Microarray analysis of liver samples showed arsenic induced aberrant gene expression including steroid-related genes, cytokines, apoptosis-related genes and cell cycle-related genes. In particular, the expression of the estrogen receptor-alpha (ER-alpha), and cyclin D1 genes were markedly increased. RT-PCR and immunohistochemistry confirmed arsenic-induced increases in hepatic ER-alpha and cyclin D1 transcription and translation products, respectively. Arsenic induced hepatic global DNA hypomethylation, as evidenced by 5-methylcytosine content of DNA and by the methyl acceptance assay. Arsenic also markedly reduced the methylation within the ER-alpha gene promoter region, as assessed by methylation-specific PCR, and this reduction was statistically significant in 8 of 13 CpG sites within the promoter region. Overall, in controls 28.3% of the ER-alpha promoter region CpG sites were methylated, but only 2.9% were methylated after chronic arsenic exposure. Thus, long-term exposure of mice to arsenic in the drinking water can induce aberrant gene expression, global DNA hypomethylation, and the hypomethylation of the ER-alpha gene promoter, all of which could potentially contribute to arsenic hepatocarcinogenesis.

Animals↗
PubMed1992

Alterations of mitogenic responses of mononuclear cells by arsenic in arsenical skin cancers.

We have studied the endemic occurrence of chronic arsenism in a limited area on the southwest coast of Taiwan. The effects of arsenic on the mitogenic responses of mononuclear cells (MNC) derived from patients with arsenical skin cancers in that area were evaluated. The subjects enrolled in this study included patients with 1) Bowen's disease, 2) arsenical skin cancers (basal cell carcinoma and squamous cell carcinoma), 3) non-arsenical skin cancers (basal cell carcinoma and squamous cell carcinoma), 4) nasopharyngeal cancer and 5) healthy controls from endemic and non-endemic areas. Phytohemagglutinin (PHA) stimulated [3H]thymidine incorporation in MNC in all groups except the arsenical skin cancer group. However, when a low concentration of As2O3 (2.5 x 10(-7) M) was added to PHA-stimulated MNC, a tremendous amplification of the uptake of [3H]thymidine was noticed in patients with arsenical skin cancer. In this study, this phenomenon did not occur in cancers not related to arsenic. This result shows that arsenical carcinomas are hyperreactive to its specific etiology--arsenic. Arsenic seems to play a role as a co-stimulant of PHA similar to interleukin-1.

Arsenic↗
PubMed1990

Assessment of occupational exposure to inorganic arsenic based on urinary concentrations and speciation of arsenic.

An analytical speciation method, capable of separating inorganic arsenic (As (V), As (III] and its methylated metabolites (MMAA, DMAA) from common, inert, dietary organoarsenicals, was applied to the determination of arsenic in urine from a variety of workers occupationally exposed to inorganic arsenic compounds. Mean urinary arsenic (As (V) + As (III) + MMAA + DMAA) concentrations ranged from 4.4 micrograms/g creatinine for controls to less than 10 micrograms/g for those in the electronics industry, 47.9 micrograms/g for timber treatment workers applying arsenical wood preservatives, 79.4 micrograms/g for a group of glassworkers using arsenic trioxide, and 245 micrograms/g for chemical workers engaged in manufacturing and handling inorganic arsenicals. The maximum recorded concentration was 956 micrograms/g. For the most exposed groups, the ranges in the average urinary arsenic speciation pattern were 1-6% As (V), 11-14% As (III), 14-18% MMAA, and 63-70% DMAA. The highly raised urinary arsenic concentrations for the chemical workers, in particular, and some glassworkers are shown to correspond to possible atmospheric concentrations in the workplace and intakes in excess of, or close to, recommended and statutory limits and those associated with inorganic arsenic related diseases.

Arsenic↗
PubMed1988

Arsenic and Raynaud's phenomenon. Vasospastic tendency and excretion of arsenic in smelter workers before and after the summer vacation.

Occupational and environmental exposure to inorganic arsenic is associated with the occurrence of Raynaud's phenomenon and objectively registered abnormal finger systolic blood pressure at local cooling (FSP). A subnormal FSP during cooling indicates a vasospastic tendency. It is not known whether these phenomena are related to recent or historical long-term exposure to arsenic. Twenty-one workers from a Swedish smelter were selected on the basis of exposure to arsenic dust for more than 14 years and a previously (three years earlier) recorded subnormal FSP during local cooling. The workers were examined before and after a 4 to 8 week summer vacation. After this intermission in arsenic exposure the urinary excretion of arsenic decreased to normal values, whereas the vasospastic reaction in the fingers remained. Thus the vasospastic tendency seems to be unrelated to the most recent urinary arsenic levels. FSP levels on cooling were significantly increased as compared with the measurements made three years earlier. This suggests a gradual improvement in finger blood circulation caused by decreased exposure to arsenic as evaluated over a time period of several years. The data thus indicate that peripheral vascular disturbances caused by arsenic are dependent on long-term arsenic exposures and are independent of short-term fluctuations in arsenic exposure.

Arsenic↗
PubMed2006

Response of arsenic-induced oxidative stress, DNA damage, and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats.

Arsenic and its compounds cause adverse health effects in humans. Current treatment employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised by number of limitations due to their lipophobic nature, particularly in case of chronic poisoning. Combination therapy is a new approach to ensure enhanced removal of metal from the body, reduced doses of potentially toxic chelators, and no redistribution of metal from one organ to another, following chronic metal exposure. The present study attempts to investigate dose-related effects of two thiol chelators, DMSA and one of its new analogues, monoisoamyl dimercaptosuccinic acid (MiADMSA), when administered in combination with the aim of achieving normalization of altered biochemical parameters suggestive of oxidative stress and depletion of inorganic arsenic following chronic arsenic exposure. Twenty-five adult male Wistar rats were given 25 ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 0.3 mmol/kg (orally) when administered individually or 0.15 mmol/kg and 0.3 mmol/kg (once daily for 5 consecutive days), respectively, when administered in combination. Arsenic exposure led to the inhibition of blood delta-aminolevulinic acid dehydratase (ALAD) activity and depletion of glutathione (GSH) level. These changes were accompanied by significant depletion of hemoglobin, RBC and Hct as well as blood superoxide dismutase (SOD) acitivity. There was an increase in hepatic and renal levels of thiobarbituric acid-reactive substances, while GSH:GSSG ratio decreased significantly, accompanied by a significant increase in metallothionein (MT) in hepatocytes. DNA damage based on denaturing polyacrylamide gel electrophoresis revealed significant loss in the integrity of DNA extracted from the liver of arsenic-exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.

Animals↗
PubMed2005

Arsenic removal from high-arsenic water by enhanced coagulation with ferric ions and coarse calcite.

Arsenic removal from high-arsenic water in a mine drainage system has been studied through an enhanced coagulation process with ferric ions and coarse calcite (38-74 microm) in this work. The experimental results have shown that arsenic-borne coagulates produced by coagulation with ferric ions alone were very fine, so micro-filtration (membrane as filter medium) was needed to remove the coagulates from water. In the presence of coarse calcite, small arsenic-borne coagulates coated on coarse calcite surfaces, leading the settling rate of the coagulates to considerably increase. The enhanced coagulation followed by conventional filtration (filter paper as filter medium) achieved a very high arsenic removal (over 99%) from high-arsenic water (5mg/l arsenic concentration), producing a cleaned water with the residual arsenic concentration of 13 microg/l. It has been found that the mechanism by which coarse calcite enhanced the coagulation of high-arsenic water might be due to attractive electrical double layer interaction between small arsenic-borne coagulates and calcite particles, which leads to non-existence of a potential energy barrier between the heterogeneous particles.

Arsenic↗
PubMed2002

Survey of arsenic in food composites from an arsenic-affected area of West Bengal, India.

An investigation of total arsenic in food composites, collected from the villagers, was carried out in arsenic-affected areas of the Murshidabad district, West Bengal where the agricultural system is mostly groundwater dependent. The shallow, large-diameter tubewells installed for agricultural irrigation contain an appreciable amount of arsenic (mean 0.085 mg/l, n=6). Even the soil is arsenic-contaminated (mean 11.35 mg/kg, n=36), so some arsenic can be expected in the food chain from crops cultivated in this area. The results revealed that the individual food composite and food groups containing the highest mean arsenic concentrations (microg/kg) are potato skin (292.62 and 104), leaf of vegetables (212.34 and 294.67), arum leaf (331 and 341), papaya (196.50 and 373), rice (226.18 and 245.39), wheat (7 and 362), cumin (47.86 and 209.75), turmeric powder (297.33 and 280.9), cereals and bakery goods (156.37 and 294.47), vegetables (91.73 and 123.22), spices (92.22 and 207.60) and miscellaneous items (138.37 and 137.80) for the Jalangi and Domkal blocks, respectively. Arsenic is absorbed by the skin of most of the vegetables. The arsenic concentration in fleshy vegetable material is low (mean 2.72 microg/kg, n=45). Higher levels of arsenic were observed in cooked items compared with raw. Daily dietary intakes of arsenic (microg) from the foodstuffs for adults are 171.20 and 189.13 and for children are 91.89 and 101.63 in the Jalangi and Domkal blocks, respectively.

Adult↗
PubMed2003

Determinants of inorganic arsenic methylation capability among residents of the Lanyang Basin, Taiwan: arsenic and selenium exposure and alcohol consumption.

The objective of this study was to assess individual variation in inorganic arsenic methylation capability and the association between selenium levels in urine and blood, and inorganic arsenic methylation capability among residents of the Lanyang Basin who drank groundwater and were exposed to high concentrations of inorganic arsenic. According to the arsenic concentration of their drinking water, they were equally and randomly classified into four groups of 252 persons. It turned out that the higher the concentration of arsenic in well water was and thus the cumulative arsenic exposure, the higher the total inorganic arsenic metabolites in urine (total As(i)) and the overall inorganic and organic arsenic in urine (overall As(i+o)) were. The percentage of inorganic arsenic significantly decreased and the DMA percentage significantly increased as the concentration of urinary selenium and serum alpha-tocopherol increased. It appeared that urinary selenium levels increased the metabolism by methylation of arsenic, a finding that requires further investigation.

Adult↗
PubMed2003

Risk factors for increased urinary inorganic arsenic concentrations from low arsenic concentrations in drinking water.

A large number of drinking water supplies worldwide have greater than 50 microg l(- 1) inorganic arsenic in drinking water, and there is increasing pressure to reduce concentrations. Few studies have specifically considered low concentrations of arsenic in water supplies and the significance of other factors which may contribute to increased exposure. This study aimed to investigate risk factors for increased urinary inorganic arsenic concentrations, in a population exposed to 10 - 100 microg l(- 1) of arsenic in drinking water, as well as a control population with lower arsenic concentrations in their drinking water. Inorganic arsenic in urine was used as the measure of exposure. The median drinking water arsenic concentration in the exposed population was 43.8 microg l(- 1) (16.0 - 73 microg l(- 1)) and less than the analytical limit of detection of 1 microg l(- 1) (<DL) (range<DL-8.0 microg l(- 1)) in the control group. The geometric mean urinary inorganic arsenic concentration for the exposed group was 4.24 microg l(- 1) (range<DL-18.8 microg l(- 1)) and for the control group was 1.18 microg l(- 1) (<DL-4.49 microg l(- 1)). In a random effects linear regression model, drinking water was the significant predictor of urinary inorganic arsenic concentrations with factors such as age, season and drinking water consumption important risk factors. These results show that concentrations of arsenic in drinking water, even at lower concentrations, make an important contribution to exposure. Further work is required to define the potential for absorption at these lower levels.

Adolescent↗
PubMed2002

Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water.

We investigated the evidence of a familial contribution to urinary methylation patterns in families ingesting arsenic in drinking water. Arsenic methylation can be assessed by measuring urinary levels of inorganic arsenic (InAs) and its methylated metabolites, monomethylarsonate (MMA), and dimethylarsinate (DMA). Methylation activity is reflected in the ratios: InAs/methylated arsenic (InAs/metAs) and MMA/DMA. Eleven families from Chile were selected because of their long-term exposure to very high levels of arsenic in drinking water (735-762 microg/L). Each family consisted of a father, a mother, and two children. We measured urinary arsenic and its methylated metabolites for each participant (n = 44). The intraclass correlation coefficients showed that 13-52% of the variations in the methylation patterns were from being a member of a specific family. Family correlations were calculated for father-mother, parent-child, and sibling-sibling pairs. Methylation patterns correlated strongly between siblings [r = 0.78 for InAs/metAs, 95% confidence interval (CI), 0.34-0.94; r = 0.82 for MMA/DMA, 95%CI, 0.43-0.95] compared to lower correlations in father-mother pairs (r = 0.18, r = -0.01, respectively), after adjustment for total urinary arsenic, age, and sex. Family correlations were not notably altered when adjustments were made for specific blood micronutrients (methionine, homocysteine, folate, vitamin B6, selenium, and vitamin B12 potentially related to methylation. We also report on a family pedigree with high prevalence of arsenic-induced effects. Participants from this family had low InAs/metAs values, which is consistent with increased toxicity of trivalent methylated arsenic species. Despite our small sample size, we observed that methylation patterns aggregate in families and are correlated in siblings, providing evidence of a genetic basis for the variation in arsenic methylation. Larger studies with more extensive pedigrees will need to be conducted to confirm these findings.

Adolescent↗
PubMed1990

The effect of variable environmental arsenic contamination on urinary concentrations of arsenic species.

Urinary arsenic species have been determined for approximately 3000 urine samples obtained from residents of a community surrounding an arsenic-emitting copper smelter. Levels of inorganic, monomethylated and dimethylated arsenic species ranged from less than 1 microgram/L (the instrumental detection limit) to 180 micrograms/L seen for dimethyl arsenic. Comparison of a subsample of this population that had the least environmental contamination with the subsample having highest environmental arsenic concentrations showed small but statistically significant differences in urinary arsenic levels for all species except dimethylated arsenic. However, for children under 7 years of age living in areas with increased environmental arsenic contamination, there was a larger and equally significant (p less than 0.001) increase in all urinary species. This effect was more pronounced in males (5-fold increase in median sum of species concentration over control group) than in females (2-fold increase in median sum of species concentration over control group) and was observed as a weaker effect in the next higher age group (7-13 years of age). Reported consumption of seafood also was significantly related to increased urinary dimethyl arsenic, but changes in distribution among the urinary arsenic species detected was not a sensitive indicator of recent seafood consumption.

Arsenic↗
PubMed1980

Mathematical model of mean age, mean arsenic dietary dose and age-specific prevalence rate from endemic chronic arsenic poisoning: a human toxicology study.

The aim of this investigation was to develop a mathematical model of mean age, mean arsenic dietary dose, and age-specific prevalence rate for endemic chronic arsenic poisoning. Data on mean age (years), mean arsenic dietary dose (mg/kg body weight/day), and age-specific prevalence rate per 100,000 population for endemic chronic arsenic poisoning in Antofagasta Commune, northern Chile, for the 1968-1971 period, were collected. Endemic chronic arsenic poisoning means here chronic arsenical dermatosis associated with marked or sever symptoms (or signs) of chronic arsenic poisoning (chronic diarrhoea, hepatic cirrohsis, chronic bronchitis, bronchiectasis, recurrent broncho-pneumonia, cardiomegaly, systemic occlusive arterial disease, cerebral thrombosis, etc.) There was a strong positive correlation between age-specific prevalence rate per 100,000 population and mean arsenic dose (r = + 0.9593) and a negative correlation between prevalence rate and mean age (r = 0.8789). These findings show that the prevalence rate declines with the advancing age and increases with the increase of arsenic dose. A multiple linear regression model E(y) = alpha + beta X1 + gamma X2, where y represents the age-specific prevalence rate per 100,000 population, X1 the mean arsenic dose, and X2 the mean age, was fitted to the data. The estimates of the parameters (alpha, beta, and gamma) were obtained by minimizing the residual sum of squares sigma(y - alpha - beta X1 - gamma X2)2. The following multiple linear regression equation was obtained: Y = 202.161 + 8452.455 X1 - 2.394 X2. Of the total variability in the prevalence rate, 96.22 per cent was accounted for by the multiple regression.

Adolescent↗
PubMed2002

Treatment and toxicokinetics of acute pediatric arsenic ingestion: danger of arsenic insecticides in children.

OBJECTIVES: To describe the toxicokinetics and management of acute pediatric arsenic ingestion. DESIGN: Case report and literature review. SETTING: Tertiary pediatric intensive care unit, St. John's Children's Hospital, Springfield, IL. PATIENT: A 22-month-old boy ingested approximately twice the estimated lethal dose of arsenic trioxide (As(2)O(3)) ant bait. Only one household arsenical insecticide is available in the United States and is presumed to be shielded from human exposure. He survived without detectable sequelae. Initially, the patient developed signs of acute hemodynamic compromise with tachycardia, hypertension, gastrointestinal symptoms, and poor urine output. He became lethargic with muscle weakness and was somnolent but never developed encephalopathy, seizures, or late onset peripheral neuropathy. INTERVENTIONS: He was stabilized with fluid resuscitation, placed on a sodium bicarbonate intravenous drip, and treated with intramuscular dimercaprol (British anti-Lewisite), 5 mg/kg every 6 hrs for 3 days. When the British anti-Lewisite and the sodium bicarbonate drip were discontinued, oral meso 2,3-dimercaptosuccinic acid (Succimer) was administered three times a day for 5 days and thereafter twice daily until the urine arsenic concentration decreased below 50 microg/L. MEASUREMENTS AND MAIN RESULTS: Continuous monitoring in the pediatric intensive care unit included continuous electrocardiogram, arterial blood pressure, urine output, vital signs, arterial blood gases, serum and urine arsenic concentrations, electrolytes, electromyography, and determination of arsenic toxicokinetics. The child's serum arsenic concentration was the highest ever reported with survival. CONCLUSIONS: Recovery from arsenic poisoning was attributable to the restoration and maintenance of adequate cardiac output and renal perfusion in early shock, which allowed depot intramuscular British anti-Lewisite to circulate and eliminate the poison. Although an intravenous antiarsenical chelating agent would be advantageous in treating shock from arsenic poisoning, none is currently available. We urge the immediate use of British anti-Lewisite therapy on patient presentation with suspected toxic arsenic ingestion.

Journal Article↗
PubMed2002

Systemic availability of arsenic from oral arsenic-trioxide used to treat patients with hematological malignancies.

AIMS: Arsenic trioxide (As2O3) is increasingly used to treat hematological malignancies. This involves daily intravenous (i.v.) administration for 4-8 weeks, with its attendant drawbacks: inconvenience, risks and expense of maintaining suitable vascular access and hospitalization. We therefore developed an oral formulation, administered it to patients and set out to assess the resulting systemic bioavailability of arsenic. METHODS: With ethics committee approval, nine patients with refractory/relapsed acute myeloid leukemia were recruited after giving informed consent. On day 1, each received 10 mg As2O3 by i.v. infusion over 1 h. Each patient swallowed 10 mg As2O3 in 10 ml oral solution 24 h later (day 2) and on subsequent days thereafter. Prior to and until 48 h post-i.v. dosing, timed venous blood samples were drawn and corresponding plasma and whole blood arsenic concentrations were determined by atomic absorption spectroscopy. Systemic bioavailability was inferred from the area under the arsenic level versus time curve (AUC) using the trapezoidal rule. Day-1 AUC after i.v. dosing was taken to be 100% and that attributed to oral dosing (day 2) was then calculated. The 48-h arsenic levels in blood cells were calculated using hematocrit values and corresponding plasma and whole blood arsenic concentrations. RESULTS: Respective day-2 mean plasma and blood AUCs attributed to oral dosing were 99% and 87% of corresponding day-1 values. On average, 48-h blood cell arsenic levels were 270% greater than in plasma ( P=0.013). No patient suffered unexpected complications, and five went into remission. CONCLUSIONS: Compared with i.v. dosing, our oral As2O3 formulation was more convenient and cost effective, and the ensuing systemic bioavailability of arsenic appeared similar. Arsenic seemed to be concentrated in the cellular fraction of blood 48 h after starting As2O3 treatment.

Acute Disease↗
PubMed2004

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.

Animals↗
PubMed1991

Occupational and environmental exposure to arsenic--increased urinary arsenic level in children.

The sum of concentrations of inorganic arsenic, methylarsonic acid (MMAA) and dimethylarsinic acid (DMAA) in urine from adults and children living in an unpolluted area was compared with the corresponding sum measured in urine from adults and children living in an area polluted with arsenic and in urine from persons occupationally exposed to arsenic. The median values for 22 adults and 10 children aged 3-10 years living in the unpolluted area were 9.3 and 19.8 nmol As/mmol creatinine, respectively. The corresponding ranges were 3.2-27.9 and 7.7-57.8 nmol As/mmol creatinine, respectively. The difference between adults and children was tested by Mann-Whitney's non-parametric test and found to be significant (p less than 0.0025). No significant difference was found in arsenic concentration in urine from 73 adults and 10 children living in the polluted area compared with the arsenic concentration in urine from those living in the unpolluted area. The arsenic level in urine from adult workers handling arsenic-treated wood was approximately four-fold higher (p less than 0.001), with a maximum recorded concentration corresponding to 814.9 nmol As/mmol creatinine. The arsenic levels in urine from two glass workers were nine- and two-fold higher, respectively. No significantly increased arsenic levels were found in urine from workers impregnating wood and in urine from lead accumulator workers.

Adult↗