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[Studies on arsenic metabolism (XX). Arsenic accumulation in the organs and excretion into the feces and urine of rats chronically poisoned with arsenic (author's transl)].

Male and female rats (60 approximately 80 g) of Wistar strain were randomly divided into two groups and were given milk and cereal diets, respectively. Each group was further divided into two groups; one was given the diet containing 100ppm of arsenic trioxide and the other a diet containing "arsenic compound" (100ppm as arsenic trioxide). Each group included five rats of both sexes. A 6-month feeding of the test diet was followed by provision of a normal diet. The accumulated arsenic was excreted almost 100% from the brain and 20 approximately 30% from organs such as kidney, liver, spleen and lung. The arsenic level persisted in tissues in animals on the cereal diet, as compared with those fed the milk diet. There was no significant difference in the accumulation and excretion of arsenic between the groups given arsenic trioxide or "arsenic compound".

Animals

[Arsenic metabolism. (17) Studies of placental transfer of arsenic and the effects of antidotes and diet].

Albino rats of Wistar strain (Tamura 1950) breeded in a closed colony were administered arsenic trioxide orally during pregnancy (from the 0 day to the 20th day). Organs of fetuses and mother rats were exenterated on the 21st day of gestation and the contents of arsenic measured using an arsenic analyzer unit with atomic absorption spectrophotometry. Whole organs of the fetus were separated into 3 groupings i.e. liver, brain and remaining organs. The contents of arsenic in the organs in each of these groupings and in the placenta were measured. Even in the non-administered group, arsenic was detected in the every organ. In the arsenic administered group, the content of arsenic in the placenta was the highest among the four preparations tested; and the content in the liver and remaining organs was considerably high, but was low in the brain. The level of accumulation of arsenic differed between each organ. In the placenta, the accumulation reached a plateau, and in the brain this accumulation was below one-tenth that in the liver. In the non-administered group, arsenic was detected in the liver, kidney, spleen and brain of mother rats. In the group on arsenite, the content in the kidney and spleen was large, followed by a large amount in the liver and in the brain respectively. The level of accumulation of arsenic in mother rats differed between each organ. Arsenite was administered with antidotes such as dimercaprol, thioctic acid and L-ascorbic acid during pregnancy (from the 0 day to the 5th day). In this group the content of arsenic in the remaining organs was statistically less than that of the control group. The content in the brain was slightly reduced by a co-administration of the antidotes, however, there was no statistical difference in the placenta and liver between the antidote-treated and control groups. The content of arsenic in the kidney of mother rats treated with antidotes was statistically less than that of the controls. Whether or not the content of arsenic in organs of fetuses and mother rats was affected by a milk diet was also studied. The content of arsenic in the organs of fetuses showed no statistical difference between the animals on an Oriental stock diet group and those on the milk diet. On the other hand, the content of arsenic in the kidney of mother rats on the milk diet was statistically less than seen in those in the Oriental stock diet group.

Animals

Airborne arsenic exposure and excretion of methylated arsenic compounds.

First void urine samples were collected from copper smelter workers exposed to inorganic arsenic and from unexposed controls. Arsenic compounds (As (III), As (V), methylarsonic acid and dimethylarsinic acid) in these samples were analyzed by selective volatilization as arsines with determination of arsenic by plasma excitation emission spectrometry. On the day preceding the urine sample collection a breathing zone measurement was made of respirable arsenic particulates for each subject. It was found that all of the subjects, including the controls excreted arsenic primarily as methylated species. Approximately 50% of the total arsenic was excreted as dimethylarsinic acid and 20% as methylarsonic acid. Slight differences in the proportion of various arsenic compounds were observed with varying levels of inorganic arsenic exposure. Amounts of arsenic species were all closely correlated with each other and with exposure. Irrespirable particulate exposures were measured on a subset of high exposure workers. Irrespirable arsenic was found to be more closely correlated with excretion of arsenic compounds than was respirable arsenic.

Adult

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

Tissue distribution of arsenic after subcutaneous implantation of arsenic trioxide pellet in rats.

In control rats, the arsenic level in the spleen and blood cells was 1.59 and 10.79 microgram/g wet tissue, respectively. In the kidney, lung, heart, brain, and hair, the arsenic level was lower than 1.1 microgram/g wet tissue. In rats in which a pellet containing 2 mg of arsenic tsioxide was implanted subcutaneously, the arsenic level in the spleen and blood cells was markedly high for at least 2 months after implantation; after 67 days of implantation, the arsenic level in the spleen and blood cells was 16.79 and 66.34 microgram/g wet tissue, respectively. In the kidney, liver, lung, heart, brain, and hair, the increase in arsenic after implantation was smaller than that in the spleen. In the plasma, arsenic was not detected before and after arsenic implantation. It is concluded that arsenic implanted subcutaneously concentrates in the blood cells, possibly in the red cells, in rats.

Animals

[Metabolism of arsenic (15). Influence of arsenic antidotes on intestinal absorption of arsenic trioxide].

A loop ligated at both sides was made in the ilecoecal portion of rabbit intestine. As2O3 solution was infused into this loop and the blood circulating around this loop was collected from the cannulated vein. As2O3 content absorbed in blood as well as that remaining in this loop were determined. In control rabbits on no drugs, approx. 30% of As2O3 infused was absorbed into the blood in 60 minutes. However, in rabbits on parenteral dimercaprol (BAL) or thioctic acid (TA), the content of As2O3 absorbed into the blood decreased remarkably while the content of As2O3 remaining in the loop increased. On the other hand, even when BAL or TA were added directly into thip loop containing As2O3, the content of As2O3 absorbed in blood decreased markedly, compared with that of the control group. Thus it was demonstrated that BAL or TA combined with AsO3(3-) after being excreted into the intestinal tract from the bile-duct, bringing about inhibition of the enteral absorption of As2O3.

Animals

Massive arsenic poisoning--effect of hemodialysis and dimercaprol on arsenic kinetics.

In massive arsenic poisoning, the use of hemodialysis and dimercaprol (BAL) therapy is still controversial. Hemodialysis is thought of value only for supportive care. BAL therapy has been criticized because of its delayed action, its own toxicity and its possible influence on arsenic clearance during hemodialysis. We studied arsenic kinetics during an acute suicidal intoxication (10 g of sodium arsenate). Treatment included gastric lavage, oral charcoal and supportive measures. Hemodialysis was performed immediately and repeated the next day. BAL therapy was prescribed only on the second day. Cardiovascular collapse, anuria and hepatic disturbance recovered in a few days and the patient could be discharged on the 15th day. Instantaneous serum arsenic hemodialysis clearance was 85 +/- 75 ml/min without previous BAL injection and 87.5 +/- 75 ml/min with a previous 250 mg BAL injection (difference not significant) indicating that BAL did not impede arsenic dialysis. The calculated total hemodialysis clearance of arsenic was higher than mean serum hemodialysis clearance indicating that erythrocyte bound arsenic is also eliminated during dialysis. We propose to consider early hemodialysis as an elimination measure in massive arsenic poisoning and to choose BAL as a chelator when dialysis is required.

Adult

Relation between airborne arsenic trioxide and urinary excretion of inorganic arsenic and its methylated metabolites.

The relation between exposure to As2O3 fumes and dust, and the urinary excretion of inorganic arsenic metabolites (monomethylarsonic acid, dimethylarsinic acid, unchanged inorganic arsenic) has been studied in 18 workers from a sulphuric acid producing plant. The concentration of arsenic in the breathing zone of each worker was measured during five consecutive days and urine samples were obtained after one shift and before the next. The collection efficiency of the air sampling system exceeded 95%. The time weighted average exposure (TWA) concentrations of As2O3 ranged from 6 to 502 micrograms As/m3 and were log normally distributed. Although exposure probably occurred by ingestion as well as inhalation, statistically significant correlations (log scales) were found between airborne TWA of As2O3 and the inorganic arsenic metabolites in urine collected immediately after the shift, or just before the next shift. For a TWA of 50 micrograms As/m3, the mean concentration of the sum of the three inorganic arsenic metabolites in a postshift urine sample amounted to about 55 micrograms arsenic/g creatinine (95% confidence interval (95% CI) 47-62). Higher estimates of urinary arsenic reported by other authors are probably due either to the influence of dietary organoarsenicals when total arsenic is measured in urine or to a low retention efficiency of the air sampling system for As2O3 in the vapour phase.

Adult

Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis.

Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAsIII) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAsIII induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAsIII comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAsIII promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.

Arsenic

The effect of seafood consumption on the assessment of occupational exposure to arsenic by urinary arsenic speciation measurements.

The determination of arsenite, arsenate, dimethylarsenic acid (DMA) and monomethylarsonic acid (MMA) in urine has been used for assessing occupational exposure to inorganic arsenic because these species were thought to be unaffected by dietary arsenic. However, this investigation reports how the consumption of certain types of seafood can lead to an increase in the amount of DMA excreted and hence an elevation in the urinary arsenic speciation total. Urine samples collected from volunteers between 4-20 hours after the ingestion of moderate-sized portions of mackerel, herring, crab or tuna, showed mean increases in the arsenic speciation totals of between 1.8 and 6.9 times compared with the levels in samples collected before the seafood was consumed. These findings have important implications in devising a biological monitoring strategy for workers exposed to inorganic arsenic.

Animals

The interaction of arsenical drugs with dihydrolipoamide and dihydrolipoamide dehydrogenase from arsenical resistant and sensitive strains of Trypanosoma brucei brucei.

D,L-dihydrolipoamide and D,L-dihydrolipoic acid react to form stable complexes with melarsen oxide with association constants of 5.47 x 10(9) and 4.51 x 10(9) M-1, respectively. These complexes possess 6-membered cyclic dithioarsenite rings which are 10-fold less stable than the 5-membered rings found in the trypanocidal drugs melarsoprol and trimelarsen, but 500-fold more stable than the 25-membered macrocyclic ring formed between melarsen oxide and dihydrotrypanothione. L-Lipoic acid concentrations in arsenical sensitive and resistant cloned lines of Trypanosoma brucei brucei have been determined by bioassay using a mutant of Escherichia coli auxotrophic for lipoate. The arsenical resistant strain was found to contain significantly less lipoic acid than the sensitive strain (19.2 +/- 4.3 and 9.7 +/- 2.9 pmol (10(8) cells)-1, respectively). The activity of the plasma membrane-associated dihydrolipoamide dehydrogenase was found to be slightly, but significantly increased in the arsenical resistant strain (34.7 +/- 1.4 and 47.8 +/- 3.7 mU mg-1, respectively). However, the Km for dihydrolipoamide and the inactivation kinetics with melarsen oxide were not significantly different between these strains. Estimates of the ratio of substrate to enzyme are of the order of 12:1 and 6:1 for arsenical sensitive and resistant strains, respectively, suggesting that these components are likely to be intimately associated with each other in the plasma membrane. These findings implicate lipoic acid, but not dihydrolipoamide dehydrogenase, in resistance to arsenical drugs, either through the mechanism of uptake or as the final target of these drugs.

Animals

Outbreak of chronic arsenic poisoning among retired workers from an arsenic mine in Japan.

Retired former workers of Matsuo Arsenic Mine of Miyazaki prefecture in Japan were subjected to extensive medical examination. The number of retired workers subjected to examination were 61 of 208 workers who were engaged in the works of the mine and were tracked down by the work rolls. These workers left the mine more than 15 years prior to the time of the examination. The main works in the mine were classified as mining, dressing of ores, refining, and clerical work. Several findings such as arsenodermatitis, depigmentation, performation of nasal septum, hyposmia, anosmia, and peripheral nervous disturbance attributed to exposure to arsenic were observed in 9 of 21 roasters who often worked in the arsenic kitchen. No characteristic findings of arsenic poisoning, that is, gastrointestinal disturbance, disorder of the cardiovascular system, hematopoietic disorders, or liver disturbance were observed in the retired workers. Another notable finding was that 8 cases diagnosed as pneumoconiosis were found in 18 miners.

Adult

Arsenic analysis II: rapid separation and quantification of inorganic arsenic plus metabolites and arsenobetaine from urine.

We describe the rapid separation of inorganic arsenic plus metabolites from arsenobetaine or seafood arsenic in urine. Traditional, high-pressure liquid chromatography is replaced by disposable silica-based cation-exchange cartridges for this separation. Both fractions are quickly separated and collected for analysis by atomic absorption spectrophotometry. Analytical recovery of both fractions is > or = 95%, with an overall precision (CV) ranging from 1.6% to 6.4%. Using this method, we correctly identified the sources of arsenic exposure, whether of inorganic or seafood origin, in 11 urine specimens supplied by the Centre de Toxicologie du Quebec.

Animals

A "pennurth of arsenic for rat poison": the Arsenic Act, 1851 and the prevention of secret poisoning.

In this country any chemist or druggist can furnish the means of self-destruction or murder for a few pence, and in too many instances have done so with the utmost indifference. The sale of a poison is regarded as a mere act of commercial intercourse; tant pis for the unfortunate victim of error or passion; he has the benefit of a coroner's inquest; the vendor of the poison receives a reprimand, and things resume their natural course--that is, arsenic and oxalic acid are retailed without compunction, and men are hurried from time to time into eternity.

Animals

[Metabolism of arsenic (Report 22). Effect of arsenic on the spontaneous motor activity, avoidance conditioning, extinction and swimming record in rats (author's transl)].

The experiments were conducted to determine the effect of arsenic on the pharmacological actions as seen in the behavior of Wistar albino rats. Nutrition during the suckling period has some apparently influence on the pharmacology behavior, we found no significant difference between the heavy (26 approximately 35g) and light (under 25g) groups. Also rats in group B1, were fed a diet which included As2O3 2 mg/kg, and rats in group B2 were fed a diet which included As2O3 15 mg/kg during the suckling period. There were no significant differences in spontaneous motor activity, avoidance conditioning and swimming record between the controls and group B1. However in group B2, the spontaneous motor activity increased as did the response on avoidance conditioning.

Animals