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Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens.

Arsenic (As) is environmentally ubiquitous and an epidemiologically significant chemical related to certain human cancers. Dimethylarsinic acid (cacodylic acid; DMA) is one of the major methylated metabolites of ingested arsenicals in most mammals. To evaluate the effects of DMA on chemical carcinogenesis, we conducted a multiorgan bioassay in rats given various doses of DMA. One-hundred twenty-four male F344/DuCrj rats were divided randomly into 7 groups (20 rats each for groups 1-5; 12 rats each for groups 6 and 7). To initiate multiple organs and tissues, animals in groups 1-5 were treated sequentially with diethylnitrosamine (100 mg/kg body weight, i.p., single dose at the commencement) and N-methyl-N-nitrosourea (20 mg/kg body weight, i.p., 4 times, on days 5, 8, 11, and 14). Thereafter, rats received 1,2-dimethylhydrazine (40 mg/kg body weight, s.c., 4 times, on days 18, 22, 26, and 30). During the same period, the animals were sequentially administered N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05% in the drinking water, during weeks 1 and 2) and N-bis(2-hydroxypropyl)nitrosamine (0.1% in the drinking water, during weeks 3 and 4; DMBDD treatment). After a 2-week interval, groups 2-5 were given 50, 100, 200, or 400 ppm DMA, respectively, in the drinking water. Groups 6 and 7, which were not given DMBDD treatment, received 100 and 400 ppm DMA during weeks 6-30. All rats were killed at the end of week 30. In the initiated groups (groups 1-5), DMA significantly enhanced the tumor induction in the urinary bladder, kidney, liver, and thyroid gland, with respective incidences in group 5 (400 ppm DMA) being 80, 65, 65, and 45%. Induction of preneoplastic lesions (glutathione S-transferase placental form-positive foci in the liver and atypical tubules in the kidney) was also significantly increased in DMA-treated groups. Ornithine decarboxylase activity in the kidneys of rats treated with 100 ppm DMA was significantly increased compared with control values (P < 0.001). In conclusion, DMA is acting as a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats, and we speculate that this may be related to cancer induction by As in humans.

Acetyltransferases↗

Embedding of laboratory wastes in clay or concrete blocks, with special reference to baking osmic acid and cacodylic acid wastes with clay.

Liquid laboratory waste containing osmic acid and cacodylic acid was mixed with potter's clay or hydraulic cement. The clay-waste product was kneaded into blocks and baked in a klin (1,200-1,400 degrees C). The cement-waste product was allowed to harden into concrete blocks. Some of the baked clay blocks and concrete blocks were ground, and immersed in 1 N NaOH or 10% HCI solutions for 3-6 months. X-ray microanalysis of the dried samples of these solutions showed that no leakage of osmium and arsenic occurred in the baked clay embedding, and that some leakage of these agents occurred in the concrete embedding. The present study indicates that the baked clay embedding method is useful for safe storage of dangerous laboratory wastes. Additional experiments suggested that glass embedding is also useful for safe storage of laboratory wastes or harmful metals.

Aluminum Silicates↗

The influence of auxin, cacodylic Acid, and amitrole on the abscission of petiole explants.

The influence of indoleacetic acid, cacodylic acid (hydroxy-dimethylarsine oxide), and amitrole (3-amino-1,2,4-triazole) on the petiole explant abscission rate was studied in three species. Indoleacetic acid increased the abscission rate in both bean (Phaseolus vulgaris L. var. Red Kidney) and Coleus (Coleus blumei Benth) at 10(-3) and 10(-4)m but had no effect on abscission in privet (Ligustrum ovalifolium). Cacodylic acid was found to stimulate abscission in explants of beans and privet, but not in Coleus. Amitrole did not stimulate abscission under any circumstance tested. In no case was the abscission rate dependent on the time at which any of the chemicals was applied. These data do not support the two-phase response of explants to applied auxin.

Journal Article↗

Internal intensity standards for heme protein UV resonance Raman studies: excitation profiles of cacodylic acid and sodium selenate.

We examine the utility of SO4(2-), ClO4-, cacodylic acid, and SeO4(2-) as internal intensity standards for Raman spectral measurements of protein structure. We find that 0.1 M SO4(2-) and ClO4- perturb the protein tertiary structure of aquomethemoglobin (met-Hb) and its fluoride (met-HbF) and azide (met-HbN3) complexes. Changes occur for the tryptophan near-UV absorption bands, the iron spin state is altered, and the fluoride ligand affinity decreases. Concentrations of ClO4- and SO4(2-) as low as 0.1 M suppress the met-HbF quaternary R----T transition induced by the allosteric effector inositol hexaphosphate (IHP). In contrast, similar concentrations of cacodylic acid and SeO4(2-) show little effect on the hemoglobin tertiary or quaternary protein structures or upon the R----T transition induced by IHP. We measure the Raman cross sections of cacodylic acid and SeO4(2-) between 218 and 514.5 nm and find that for UV excitation they are ca. 5-fold larger than ClO4- or SO4(2-). Thus, cacodylic acid and selenate can be used at lower concentrations. Cacodylic acid and SeO4(2-) are superior Raman internal intensity standards for protein structural studies.

Cacodylic Acid↗

Disposition of 14C and/or 74As-cacodylic acid in rats after intravenous, intratracheal, or peroral administration.

The distribution, excretion, and possible metabolism of (14)C- and/or (74)As-cacodylic acid, an organoarsenical herbicide, was studied in rats following a single intravenous injection, intratracheal instillation or oral gavage. Male Sherman rats were dosed at levels ranging from 200 mg/kg to 120 mug/kg. The extent and rate of lung absorption was greater than gastrointestinal absorption. Concentrations in the liver and whole blood were higher after peroral dosing than intravenous administration. Levels observed in plasma and other tissues were similar after all three routes following the absorptive phase. The percent dose found in the whole blood, red blood cells, and plasma was similar for all doses given by these routes. Less than 0.1(1/2) of the administered dose was recovered as (14)CO(2) by any route at 24 hr after administration. Twenty-four hours after intravenous, intratracheal, and peroral administration, 71, 60, and 25%, respectively, was excreted in the urine. After intravenous administration of 200 mg/kg, sufficient (14)C-cacodylic acid was recovered in bile to account for the small amount excreted in the feces. Cacodylic acid is probably not metabolized to inorganic arsenic since the disposition of (14)C and (74)As-cacodylic acid were identical.Kinetic analyses of the plasma curve for (14)C-cacodylic acid (high dose) yielded three half-times; 0.014, 0.214 and 3.42 hr with an apparent volume of distribution of 15.3 ml. Highest initial concentrations were found in the whole blood, muscle, kidney, liver and lung. Levels in all tissues decreased rapidly, but remained high in whole blood. The red blood cells were found to be the major site of body burden of cacodylic acid.

Absorption↗

The teratogenic potential of cacodylic acid in the rat and mouse.

Cacodylic acid, an organic arsenical herbicide, was administered to time-pregnant albino CD rats and CD-1 mice on days 7-16 of gestation. The compound was given by gastric intubation as a solution in distilled water. Rats received 0, 7.5, 15, 30, 40, 50, or 60 mg/kg/day in 0.2 ml/day intubation volume; mice received 0, 200, 400, or 600 mg/kg/day in 0.1 ml/day. Following maternal sacrifice on day 18 (mice) and 21 (rats), fetuses were weighed and fixed for skeletal and visceral examinations. Fetal and maternal toxicity was observed in both species. In the mouse, maternal toxicity was evident at the lowest dose, while teratogenic response was confined to cleft palate at 400 and 600 mg/kg/day. The effective maternal toxic dose in the rat was 40 mg/kg/day. In this species, incidence of irregular palatine rugae, i.e., ridges that were discontinuous and/or not lying in apposition at the palatal raphe, was significantly (p less than 0.001) dose-related. The results suggest an "apparent no effect level" for this anomaly below 30 mg/kg/day.

Animals↗

Tissue retention of arsenic in rats fed witch founder or cacodylic acid.

Weanling rats were fed one of five diets for 42 days either ad libitum or on a restricted-equalized feeding regimen. The five diets included a low arsenic control and a medium or high level of arsenic from either witch flounder (Glyptocephalus cynoglossus) tissue or cacodylic acid. Dietary arsenic in either form did not influence any of the biological indices of exposure examined except tissue arsenic levels. Retentions of arsenic in the livers and spleens of rats fed the highest level of fish arsenic (28.8 ppm) were about 7 and 2 times higher, respectively, than controls. Retentions of arsenic in the livers and spleens of rats fed the highest level of arsenic from cacodylic acid (22.1 ppm) were about 30 and 110 times higher, respectively, than controls. Retention of arsenic within the erythrocytes of rats fed the highest level of fish arsenic were equal to controls whereas it was about 130 times higher than controls among rats fed the highest level of arsenic as cacodylic acid. Apparently the chemical form of the arsenic in the edible tissue of witch flounder is uniquely metabolized by the rat compared to other arsenic forms.

Animals↗

Optically detected magnetic resonance study of the interaction of an arsenic(III) derivative of cacodylic acid with EcoRI methyl transferase.

The interaction of the enzyme Escherichia coli RI methyl transferase (methylase) with an arsenic(III) derivative of cacodylic acid has been investigated by optical detection of triplet-state magnetic resonance (ODMR) spectroscopy in zero applied magnetic field. The reactive derivative (CH3)2AsSR is formed by the reduction of cacodylate by a thiol. The As(III) derivative binds to the enzyme by mercaptide exchange with a cysteine (Cys) residue located close to a tryptophan (Trp) site. The arsenical binding selectively induces an external heavy-atom effect, perturbing the nearby Trp residue in the enzyme. Zero-field splittings (ZFS) and total decay rate constants of the individual triplet-state sublevels of the Trp residue in the presence and absence of perturbation by As(III) have been determined. The perturbed Trp shows a large reduction in the overall decay lifetime compared with unperturbed Trp residue, exhibiting a high selectively for the Tx sublevel. This selectivity suggests that the As atom lies in the xz plane of the principal magnetic axis system of Trp, but not directly along the z (out-of-plane) axis. The accessibility of this enzyme binding site to the arsenical is decreased upon forming a ternary complex of methylase with sinefungin and a DNA oligomer, d[GCGAA(BrU)(BrU)CGC], containing two 5-bromouracil (BrU) bases in place of thymine within the hexadeoxynucleotide recognition sequence. This result indicates that the arsenical binding site in methylase which produces the Trp heavy-atom effect is protected from this ligand by ternary complex formation or the enzyme undergoes a conformation change, removing the Cys from the Trp site. This protection is also observed in fluorescence quenching experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Arsenic↗