Administration Of Arsenic Research Articles

Metabolism and excretion of gallium arsenide and arsenic oxides by hamsters following intratracheal instillation

The increasing use of gallium arsenide (GaAs) in the electronics industry has produced the need for pharmacokinetic and toxicologic data on GaAs. The disposition in male Syrian golden hamsters ( n=4) following intratracheal instillation of GaAs (mean volume diameter 5.8 μm), arsenic(III) oxide (arsenite), and arsenic(V) oxide (arsenate) at a dose of 5 mg/kg body weight was examined. Blood, kidney, liver, and lung samples were collected at 1, 2, and 4 days after administration. Excreta were collected daily. Urinary metabolite profiles were determined after separation on a mixed anion-cation-exchange column. Total As content was analyzed by direct hydride flame atomic absorption spectrophotometry after digestion. Arsenic blood levels after GaAs, arsenite, and arsenate administration were 0.185 ± 0.041, 0.596 ± 0.117, and 0.310 ± 0.045 ppm, respectively, after Day 1. Arsenic blood levels after GaAs administration increased to 0.279 ± 0.021 ppm on Day 2 indicating continued absorption while levels decreased for the arsenite and arsenate groups. At Day 1 the liver contained 0.565 ± 0.036, 2.62 ± 0.26, and 0.579 ± 0.144% of the arsenic dose of GaAs, arsenite, and arsenate, respectively. The arsenite and arsenate were rapidly excreted in the urine with almost half the dose appearing after 4 days; in contrast, only about 5% of the GaAs was found at the corresponding time. Total recoveries, as arsenic equivalents, for the three compounds were between 75 and 80%. Ratios of the two major urinary metabolites (dimethylarsinic acid/total inorganic As species) were 1.41, 1.71, and 0.983 for GaAs, arsenite, and arsenate, respectively. GaAs is metabolized to the same compounds as arsenite and arsenate, and shows a metabolic profile most similar to that observed for sodium arsenite.

Arsenic metabolites in urine and feces of hamsters pretreated with PCB

High pressure liquid chromatography and graphite tube atomizing atomic absorption spectrometry were used to quantify monomethyl arsonic acid (MMA), dimethyl arsinic acid (DMA), and inorganic arsenic (IA: arsenite plus arsenate) in the urine and feces of male and female hamsters pretreated with a single ip injection of PCB (100 mg/kg) and 4 days later given a single po dose of arsenite (10 mg As/kg). Approximately 17 to 23% and 35 to 63% of the arsenic given was eliminated in the urine and feces, respectively, during the 5 days after the administration of arsenic. Both DMA and MMA were found in the urine but only MMA was detected in the feces, as methylated metabolite. Fecal excretion of arsenic was significantly larger in female than in males. PCB influenced the metabolism of arsenic by significantly increasing the proportion of DMA excreted into the urine of female hamsters during the 5 days after the arsenic administration, but did not alter the total amount of arsenic metabolites in any group of male or female hamsters. PCB did not affect the cumulative amounts of fecal arsenic in any group, although the excretion in the PCB-treated group of females reached the maximum level 1 day earlier than in the controls. These results suggest that the metabolism of arsenic may be regulated by certain sex-relating factors which are influenced by PCB.

Reduction and methylation of sodium arsenate in the rat.

After a single oral dose of sodium [74As] arsenate to male Wistar rats, arsenic was rapidly absorbed and accumulated in the blood and to a lesser extent in the liver, kidneys, lungs and spleen. Within 1 h of dosing, arsenic was present in the blood, liver and spleen predominantly in the methylated forms (methylarsonic acid and dimethylarsinic acid), whereas in the lung and kidneys, approximately 50% was in the inorganic form. Intravenous injection of sodium [74As] arsenate resulted in a pattern of arsenic species in the blood and kidneys similar to that seen after oral administration, suggesting that the gut flora does not contribute significantly to biotransformation of arsenic in vivo. Analysis of the forms of arsenic in portal blood after administration of arsenate via the small intestine revealed a rapid reduction of arsenate to arsenite, followed by linear rates of production of methylarsonic acid and dimethylarsinic acid.

Urinary excretion of inorganic arsenic and its metabolites after repeated ingestion of sodium metaarsenite by volunteers.

Arsenic (125, 250, 500 or 1000 μg as NaAsO2) was administered orally once a day for five consecutive days to 4 volunteers who refrained from eating marine organisms during the experiment. Urine was collected during 24-h periods starting one day before the first administration and up to 14 days later. The following determinations were performed: total arsenic, inorganic arsenic (As;), monomethyl arsenic (MMA) and dimethylarsinic (DMA) acids. In each case, the sum of As;, MMA and DMA approximated very closely the urinary concentration of total arsenic determined after mineralisation of the urine sample. It was concluded that these arsenicals are the only metabolic forms of arsenic following absorption of inorganic arsenic. Since a steady state in the urinary excretion of arsenic is reached within 5 days, our results demonstrated that at equilibrium, the total amount of arsenic excreted in urine per day amounts to 60% of the ingested dose. Speciation of the arsenic metabolites in urine indicated that the arsenic methylation capacity of the human body was not yet saturated, even with an oral daily dose of 1000 μg As for 5 days. However, when the administration of arsenic was stopped, the biological half life of arsenic in urine increased slightly with the dose (from 39 h at 125 μg to 59 h at 1000 μg). Determination of inorganic arsenic, MMA and DMA in urine appears to be the method of choice for the biological monitoring of workers exposed to inorganic arsenic since these measurements are not influenced by the presence of organoarsenicals from marine origin. From the linear relationship found in this study between arsenic administered and that excreted in urine, it was estimated that a time-weighted average exposure of 50 μg As/m3 would lead to an average urinary excretion of 220 μg As (sum of Asi, MMA and DMA) per gram creatinine.

The potent heme oxygenase inducing action of arsenic and parasiticidal arsenicals.

The administration of trivalent arsenic, either as sodium arsenite or as the trypanocidal drug melarsoprol, to rats produced a profound induction of microsomal heme oxygenase (EC 1.14.99.3) in both liver and kidney and a concomitant decrease in cytochrome P-450 content. In addition, perturbations of delta-aminolevulinate synthase were observed which showed an initial decline followed by a rebound increase in the activity of this enzyme with arsenical treatment. Pentavalent arsenic did not induce hepatic heme oxygenase but did induce the enzyme in kidney, although to a lesser extent (50%) than trivalent arsenic. Treatment of isolated chick embryo liver cells in vitro with sodium arsenite or the parasiticidal drug melarsoprol also showed a potent induction of heme oxygenase. These findings describe a new and potent ability of arsenic and parasiticidal arsenicals to induce heme oxygenase resulting in enhanced degradation of cellular heme.

Effects of lead and arsenic on the formation of 5β-H steroids

The concentration of 5β-H steroids was studied by measuring the changes of the activities of steroid 5β-reductase, 3α- and 3β-hydroxy steroid dehydrogenase and β- d-glucuronidase following the administration of lead or arsenic. After lead administration, Δ 4-androstene-3,17-dione 5β-reductase activity showed a significant increase. 3α -hydroxy steroid dehydrogenase activity showed little change, but 3β-hydroxy steroid dehydrogenase activity increased slightly. After arsenic administration, testosterone, Δ 4-androstene-3,17-dione, progesterone and 17α-hydroxy progesterone 5β-reductase activities showed a significant increase. 3α-Hydroxysteroid dehydrogenase activity with androsterone as substrate also increased significantly. 3β-Hydroxysteroid dehydrogenase activity increased slightly. From these results, it is suggested that in lead and arsenic poisoning some 5β-H steroids are increased and played a rôle in causing an increase of δ-aminolevulinic acid (ALA).

Effects of concurrent administration of lead, cadmium, and arsenic in the rat

Humans are exposed to a number of toxic elements in the environment; however, most experiments with laboratory animals investigate only one toxic element. To determine if concomitant exposure to lead (Pb), cadmium (Cd), and/or arsenic (As) modified the changes produced by any one metal in various parameters of toxicity, 168 male, Sprague-Dawley, young adult rats were fed nutritionally adequate diets to which had been added 0 or 200 ppm Pb as Pb acetate, or 50 ppm Cd as Cd chloride, or 50 ppm As as sodium arsenate or arsanilic acid in a factorial design for a period of 10 weeks. At these concentrations, Cd and As reduced weight gain even when differences in food intake were taken into account; administration of both Cd and As depressed weight gain more than did either metal alone. Pb did not adversely affect food consumption or weight gain. Increased numbers of red blood cells (RBCs) were observed following administration of Pb, Cd, or As; usually more cells were observed when two or three metals were administered, compared to individual metals. Despite increasing numbers of circulating RBCs, hemoglobin and hematocrit were reduced, especially with the Pb-Cd combination and the Cd-arsanilic acid combination. Specific effects of Pb on heme synthesis were observed, including increased urinary excretion of delta-aminolevulinic acid; this increase was reduced by the presence of dietary cadmium. Analyses of blood showed values for the laboratory rat within normal ranges for blood urea nitrogen, creatinine, cholesterol, calcium, albumin, total protein, and bilirubin. Uric acid was increased by Pb, with little modification by dietary Cd or As content. Serum glutamate-oxalate transaminase activity was reduced by As. Serum alkaline phosphatase was greatly reduced by either As or Cd but not Pb. Combinations of As and Cd did not further reduce the activity of this enzyme. Kidney weight and kidney weight/body weight ratios were increased by Pb alone, with no effects of Cd or As alone or as interactions. Liver weight/body weight ratios were reduced in animals fed 50 ppm dietary Cd. Kidney histology shows predominantly Pb effects, namely, intranuclear inclusion bodies and cloudy swelling. Ultrastructural evaluation of kidneys from Pb-treated animals disclosed nuclear inclusion bodies of the usual morphology and mitochondrial swelling. Concurrent administration of Cd greatly minimized Pb effects on the kidney under conditions of this experiment. Liver histology suggests an increased rate of cell turnover with either As compound, but few specific changes.

Effects of arsenic, mercury, thallium, and lead on selenium metabolism in rats

Arsenic, mercury, and thallium all inhibited the pulmonary excretion of volatile selenium compounds by rats injected with subacute doses of sodium selenite. Lead had no effect on selenium volatilization. Mercury increased the retention of selenium in the blood, kidneys, and spleen; thallium increased the retention of selenium in the kidneys and liver. The biliary excretion of selenium was stimulated severalfold by the administration of arsenic, but not by mercury, thallium, or lead. Arsenic improved the growth of rats chronically poisoned by selenium, largely prevented the liver damage caused by selenium, and decreased the amount of selenium retained in the tissues. Neither thallium nor mercury protected against chronic selenosis.

Effect of oxidative phosphorylation inhibitors on synthesis of liver mitochondria phospholipids.

The effect of single doses of arsenate, bilirubin, dinitrophenol, and oligomycin on synthesis of mitochondria phospholipids of liver of rats was studied. A statistically significant decrease occurred in synthesis of phosphatidyl inositol, sphingomyelin, lecithin, phosphatidyl serine, and phosphatidyl ethanoiamine of liver mitochondria following administration of dinitrophenol. Administration of arsenate, oligomycin, and bilirubin inhibited statistically the incorporation of the isotope into all the phospholipid fractions of liver mitochondria except sphingomyelin and phosphatidyl inositol. However, oligomycin inhibited incorporation of the isotope into the sphingomyelin fraction and arsenate inhibited the phosphatidyl inositol fraction. (auth)

Photosensitization to coal tar. A cause of psoriatic erythroderma.

Erythroderma is a rare and dramatic complication of psoriasis. It can be precipitated by infection, pregnancy, systemic administration of arsenic, antimalarials, and corticosteroids, as well as topical medicaments. 1-3 The purpose of this paper is to report a case of psoriatic erythroderma as a complication of allergic contact dermatitis to coal tar, in which the relationship of sunlight to this condition is shown by photoskin tests . Report of Cases A 37-year-old truck driver with a 20-year history of chronic psoriasis was admitted in January, 1960, to the hospital for the Goeckermann regimen, consisting of coal tar, baths, and ultraviolet light. He had been treated previously with coal tar on numerous occasions without any adverse effects. On the second day of therapy, after having received 2 minutes of hot quartz ultraviolet light to the entire body, he developed an acute erythema, identical to a first degree sunburn, which rapidly developed into

Hyperadrenocorticism with arsenic; a physiological basis of therapy with arsenite solution.

1. Administration of arsenic (mapharsemine) to rats gives rise to a high plasm level of corticosterone and increases the content of corticoids of the same fraction in adrenal glands, while in rats intoxicated with phosphorus or with lead, the level of corticosterone in plasma and the content of corticoids in the same fraction of adrenal glands are decreased.In every case of intoxication i. e. with arsenic, phosphorus and lead, corticoids of the so-called Fk-fraction greatly increase in plasma as well as in adrenal glands, meanings which are not yet clear.2. When arsenite solution is administered to normal subjects and to patients after the prescription, the levels of hydrocortisone and corticoids of Bk-fraction rise in plasma and the urinary excretion of 17-OH-corticosteroids increases gradually with the time of medication. One of the physiological bases of therapy with arsenic must be in stimulation of the adrenocortico-pituitary function.

Aetiology of Post-arsphenamine Jaundice

Damage to the liver parenchyma, with or without icterus, can occur at any stage of untreated syphilis, acquired or prenatal. Icterus is rare in early acquired syphilis, and when it appears is usually coincident with secondarv manifestations, original or relapse. The liver biopsy findings in cases of jaundice in untreated secondary syphilis are indistinguishable from those seen in cases of post-arsphenamine jaundice. Liver material from untreated secondary syphilitics who show no clinical signs of liver damage is quite normal. Jaundice in untreated cases, though of some interest, is of less importance than the icterus which appears after arsenical treatment has been started. This type of frequently referred to as post-arsphenamine jaundice, differs from the jaundice of untreated early syphilis in certain respects. In the latter type the use of arsphenamines in treatment is, in our experience, without danger and leads to a rapid clearing of the icterus. This is not so in the case of post-arsphenamine jaundice. Although many cases have been described in which arsenical treatment has been continued through post-arsphenamine we are convinced that such a policy is dangerous. The administration of arsenic before clinical and biochemical recovery in some such cases has produced alarming evidence of increased liver damage. Milian (1934), who believed that the delayed jaundice of arsphenamine treatment is due not to the drug but to a hepatic recurrence of syphilis, continued to treat 75 cases with arsphenamine, and claimed satisfactory results in 66. Of the remainder, 11 were intolerant and 4 died. Goodman and Gilman (1941) thought that jaundice during arsphenamine treatment may be due to one or a combination of the following factors-the drug, syphilis itself, or intercurrent infection. The evidence is convincing that many cases represent attacks of non-specific catarrhal jaundice occurring in patients whose livers are subjected to the added insults of syphilis and an arsenical. Mitchell (1943), reporting on jaundice in syphilitics under treatment in the Canadian Army in Great Britain, suggested that jaundice is due to the association of two hepatoxic agents-the arsenic and the agent or toxin of infectious hepatitis in patients under arsenotherapy. These two opinions imply that the infectious hepatitis or non-specific catarrhal jaundice (other synonyms-toxic hepatitis, non spirochaetal epidemic simple acute catarrhal jaundice) associated with arsenical treatment in syphilitics is identical with that which produces jaundice so frequently in the normal population and which has become so prevalent in recent years. Two Types of Hepatitis

Idiopathic Ulcerative Colitis

ULCERATION of the colon may occur from any one of many causes. Organisms within the colon may produce mild or severe grades of inflammation and ulceration. To this type belong Endamœba histolytica, dysentery bacilli, and the bacilli of tuberculosis. As the colon is an organ of excretion, ulceration may occur as the result of the excretions of disease toxins, poisons, and drugs. Colonic ulceration is occasionally seen in the terminal stages of nephritis, also after the administration of arsenic and mercurochrome. Among the various types of ulceration of the colon is one described as idiopathic ulcerative colitis. This disease has a definite clinical picture, typical roentgen-ray findings, and a characteristic sigmoidoscopic appearance. It was first mentioned by Wilkes and Moxon in 1875, and first described by White in 1888, although Hawkins believes the “pedigree” of this disease can be traced back nearly three hundred years to the “blood flux” of Sydenham in 1669. Most patients with this disease can defin...

The Treatment of Surra in Horses by Means of Arsenic and its Derivatives

The value of arsenic in the treatment of trypanosomiasis is no new discovery.Evans (1880), who described the first pathogenic trypanosome, recommended the administration of arsenic. Lingard (1899), for many years, investigated surra in India and treated twenty-one horses suffering from that disease with arsenious acid. One horse survived. His system of treatment was, the administration of arsenic in the form of Fowler's solution, commencing with 5 grains, twice daily and gradually increasing to 10 grains. Treatment extended over several months; the total amount of arsenic given, in some instances, amounted to over 2,000 grains. During the period of treatment intermissions of 30 to 50 days were recorded, but all the animals, with one exception, finally succumbed to the disease. Bruce (1897 and 1903), treating nagana in Zululand, gave 6 to 12 grains of arsenic in form of arsenite of soda to horses and asses suffering from that disease. Trypanosomes remained absent during the period of treatment, but reappeared immediately treatment ceased. Trélut (1907) claims to have cured cases of dourine by the daily administration of 3 to 6 grammes of arsenious acid. Archangeliky and Novikoff (1907) also record cases of dourine cured by them with arsenite of sodium and cacodylic acid. Marchal (1903) stated that he cured five stallions suffering from dourine by subcutaneous injections of 1 gramme of cacodylate of soda. Loeffler and Ruehs (1908) record a number of successful experiments on animals affected with nagana, which they treated with a solution of arsenious acid. They consider this solution to be a specific cure and a prophylactie for nagana. Laveran and Thiroux (1907–8) repeated these experiments and came to conclusions different form those of Loeffler and Ruehs.

LICHEN PLANUS HYPERTROPHICUS.

There are a number of names for this affection: Lichen simplex chronicus circumscriptus; lichen verrucosus, lichen corneus, etc., most of which are appropriate to this morbid process. In the last two decades it has been the subject of lively discussion, inasmuch as some cases of this description do not yield to the administration of arsenic, others do not show any typical lichen papules, but only the verrucous patches are characteristic of this disease and hence there arises serious doubt whether in these cases we have really to deal with a true lichen-planus process or with an atypical form of mycosis fungoides—A. Neiser, Deutscher Dermatologen Congress, 1894—or with a lichenization of a localized pruritus in the sense of Brocq. Thus further, Kaposi has named cases of this appearance keratosis verrucosa papillaris. Now, this question as to the identity of these with lichen planus has lately been answered in the affirmative, after