Selenite Toxicity Research Articles

Experimental selenium toxicity in guinea pigs: haematological studies.

Haematological studies were conducted in recently weaned guinea pigs fed selenium-enriched barley (organic selenium) and barley mixed with sodium selenite (inorganic selenium). An attempt was made to study the effect of sodium arsenite supplementation in sodium selenite toxicity. A significant (p less than 0.01) decrease was noticed in the mean values of haemoglobin, haematocrit, mean corpuscular haemoglobin and mean corpuscular volume thereby indicating a microcytic hypochromic anaemia. The anaemia was comparatively more marked in guinea pigs fed selenium-enriched barley than in those kept on barley mixed with sodium selenite. There was a significant decrease in total leucocyte count which was the result of lymphocytopenia in organic toxicity and a decrease in both neutrophils and lymphocytes in inorganic toxicity. Dietary supplementation with sodium arsenite resulted in less reduction in the mean values of different erythrocytic indices thereby indicating that addition of sodium arsenite has some protective effect against toxicity with sodium selenite.

Mechanims of mutagenicity and toxicity of sodium selenite (Na 2SeO 3) in in Salmonella typhimurium

The mechanisms of selenite toxicity and mutagenicity in S. typhimurium have been characterized. In contrast to previous reports, selenite toxicity was shown not to involve nonspecific incorporation into protein via the sulfur metabolic pathways. Selenite toxicity was, however, shown to involve its ability to act as an oxidizing agent, primarily through reactions with sulfhydryls. Strain which lack glutathione (GSH) are more sensitive to killing by sulfhydryl reagents. The selenite sensitivity of such a mutant was a biphasic phenomenon. The mutant was much more sensitive than a strain which contained GSM at lower selenite concentrations whereas, at higher concentrations, the mutant thus appeared to involve damage to mechanism of selenite toxicity at lower concentrations in this mutant thus appeared to involve damage to intracellular sulfhydryls. The sensitization to higher doses of selenite by GSH could be explained by the generation of toxic oxygen species. The in vitro reactions of selenite with both cyteine and GSH readily produced H 2O 2 and O 2 −. A S. typhimurium strain which overproduces superoxide dismutase (SOD) and catalase was more resistant to high concentrations of selenite, but not killing by the lower doses. Pretreatment of cells with a nonlethal dose of selenite induced the synthesis of proteins which protected the cells from killing by H 2O 2 or high doses of selenite. Selenite was also a mutagen in the tester strain TA104, in which a number of other oxidizing agents have also been found to be mutagens. These results were cosistent with a model in which the reactions of selenite and intracellular thiols with concomitant production of active oxygen species are the primary causal agents of selenite mutagenicity and toxicity in S. typhimurium.

Toxicity of organic and inorganic selenium to mallard ducklings.

The toxicity of selenomethionine and sodium selenite to mallard ducklings (Anas platyrhynchos) was measured by feeding each form from hatching to six weeks of age at dietary concentrations of 0, 10, 20, 40, and 80 ppm selenium. At 80 ppm selenium, sodium selenite caused 97.5% mortality by six weeks and selenomethionine caused 100% mortality. At 40 ppm, these two forms of selenium caused 25 and 12.5% mortality. No mortality occurred at 10 or 20 ppm. Diets containing 20, 40, or 80 ppm selenium in both forms caused decreases in food consumption and growth. The only statistically significant effect of 10 ppm selenium was with sodium selenite, which resulted in larger livers than controls. Selenomethionine was more readily stored in the liver than sodium selenite at levels above 10 ppm selenium in the diet. Based on comparisons of residues of selenium in livers of surviving and dead ducklings, concentrations in the liver were not diagnostic of death due to selenium poisoning. Because both forms of selenium resulted in severe reductions in food consumption, selenium-induced starvation may have been related to duckling mortality. It was not clear whether either form of selenium at 10 ppm in the diet resulted in a leveling off of selenium concentrations in the liver within six weeks.

Efficacy of trimethylselenonium versus selenite in cancer chemoprevention and its modulation by arsenite.

Selenite, which has been demonstrated to be an effective prophylactic agent in experimental carcinogenesis, is metabolized to trimethylselenonium as an excretory product. Previous reports in the literature have shown that arsenite decreases the toxicity of selenite but increases that of trimethylselenonium. The present study was designed to compare the anti-carcinogenic efficacy of selenite and trimethylselenonium and their interactions with arsenite in chemoprevention, using the dimethylbenz[a]anthracene-induced mammary tumor model in rats. The results of this experiment indicated that supplementation of selenite (3 p.p.m. Se) alone produced approximately 50% reduction in tumor yield, and arsenite (5 p.p.m. As) reduced the response to selenite. In contrast, arsenite greatly enhanced the protective effect of trimethylselenonium (40 p.p.m. Se); this combination was nearly as effective as selenite, although either trimethylselenonium or arsenite alone was inactive. Thus, arsenite has the capacity to influence the anti-carcinogenic action of selenium, and can either potentiate or attenuate the protective effect depending on the methylation state of the selenium compound. The metabolism of selenium and its perturbation by arsenite are discussed in relation to the above findings.

Periodate-oxidized adenosine inhibits the formation of dimethylselenide and trimethylselenonium ion in mice treated with selenite

The metabolic detoxification of selenite and many other selenium compounds involves a series of S-adenosylmethionine-dependent methylations yielding dimethylselenide (DMSe), which is exhaled, and trimethylselenonium ion (TMSe), which is excreted in the urine. This paper shows that periodate-oxidized adenosine (Adox) inhibits these methylation reactions in vivo and increases the toxicity of selenite. When Adox was injected in mice at 100 μmol/kg 30 min before injection of [ 75Se]selenite at 0.4 mg Se/ kg the appearances of [ 75Se]DMSe in the breath and [ 75Se]TMSe in the liver were completely inhibited for 90 min. This was mediated by accumulation of S-adenosylhomocysteine, the methyltransferase inhibitor, in the livers of Adox-treated mice due to inhibition of its hydrolase enzyme. During 24 h, Adox-treated mice excreted no detectable urinary [ 75Se]TMSe and exhaled only 20% as much [ 75Se]DMSe as controls. The urine of Adox-treated mice also contained S-adenosylhomocysteine at a level ( ca. 4 m m), 200 times that of untreated mice, which provided a convenient index of methylation potential in the intact animal. When three groups of three mice each were injected with 100 μmol Adox/kg, selenite at 4 mg Se/kg, or a combination of the two, the mice receiving the combination were dead within 2 days, while the mice in the other two groups all survived at least 4 days. These results verify the enzymatic nature of selenium methylation in vivo, support its importance in detoxification, and indicate the value of Adox in further studies of selenium metabolism.

Comparison of cupric and sulfate ion effects on chronic selenosis in rats.

The ameliorating effects of Cu++ and SO4--ions on concurrent selenite toxicity were compared in two factorial experiments using 60 weanling rats each. In the first experiment, 0, 500 and 1,000 mg Cu (as CuCl2)/kg diet were fed in conjunction with 0, 5, 10 and 20 mg Se (as Na2SeO3)/kg diet. In the second experiment, the treatments were 0, 500 and 1,000 mg SO4 (as Na2SO4)/kg fed in conjunction with 0, 5, 10 and 20 mg Se/kg diet. A paired-feeding experiment using 10, 15 and 20 mg Se/kg diet was also conducted with 28 rats to compare the influence of inanition in control and selenite-fed rats. Cupric++ ion, but not SO4--ion, prevented mortality among selenite-intoxicated rats. There were significant Cu X Se interaction effects on feed intake, daily gain, packed cell volume (PCV), serum Cu and Fe, sperm counts, and weights of liver, kidney and testis. There were main effects of Cu and Se on serum Se and liver Cu. In Exp. 2 there were significant SO4 X Se interaction effects on feed intake, daily gain, serum Cu and testis weight. There were main effects of Se on PCV, sperm count, serum testosterone, liver Se, liver Cu and the absolute weights of liver and kidney. The only main effect of SO4 was that of increased liver Cu concentrations. Among the pair-fed rats, the selenite-fed rats, with one exception, died before their paired rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity of sodium selenite to rainbow trout fry

In a study designed to examine the long-term effects of inorganic selenium (IV) on early life stages of rainbow trout ( Salmo gairdneri), survival was significantly reduced at selenium concentrations of 47 and 100 μg l −1 after 90 days of exposure. Length and weight were significantly reduced after 90 days of exposure to 100 μg l −1. Whole-body residues of selenium increased with increasing exposure concentrations but appeared to decline between 30 and 90 days of exposure. Analyses of trout backbone indicated little change in bone development with exposure to selenium (IV) with one exception; calcium concentrations were significantly decreased in fish exposed to ⩾ 12 μg l −1 of selenium. Results of our study indicates that a recommended safe level of 10 μg l −1 for inorganic selenium would not significantly affect growth and survival of rainbow trout; however, concentrations of selenium near this level can reduce the levels of calcium in the backbones of trout.

The effect of sodium selenite toxicity on tissue distribution of zinc, iron, and copper in rats

Male Sprague-Dawley rats were used to determine the effects of suptoxic and toxic concentrations of selenite in the drinking water on tissue distribution of zinc (Zn), iron (Fe), and copper (Cu). Se (as sodium selenite) was provided in drinking water at concentrations of 0, 2, 4, and 8 ppm. At 19 d, half of the rats in 4 and 8 ppm Sesupplemented groups were kept on drinking water alone for additional 13 d. All rats were sacrificed at the end of 32 d of experiment. Heart, liver, and kidney were analyzed for the concentrations of Fe, Zn, and Cu by atomic absorption spectrophotometry and of Se by a fluorometric method.Results indicated that rats receiving 4 and 8 ppm Se in drinking water showed a marked reduction in food intake and a reduced growth rate. These adverse effects were quickly reversed when high Se intake was discontinued. Se toxicity caused minimal change in zinc status, reduced tissue iron concentrations and caused a marked increase in copper contents in heart, liver, and kidney. The latter findings were only partly reversed after removal of Se in drinking water. The accumulation of Cu in the tissues of Se-toxic rats provides the evidence of some interaction between Se and Cu.

Effect of selenite and seleniferous fly-ash leachate on growth and viability of the marine amphipod Allorchestes compressa

Juveniles of the amphipod Allorchestes compressa Dana were exposed to sodium selenite and to seleniferous leachate from coal fly-ash. A maximum acceptable toxicant concentration (MATC) for selenite of >44<93 μg Se l-1 is indicated by the results for growth and viability. Leachate:sea water mixtures produced effects which were consistent with selenite toxicity but quantitatively less drastic than expected from the pure selenite work, perhaps because of sulphate antagonism. The results are compared with selenium toxicity data for other aquatic species, and high-light the difficulties of using application factors as the basis for water-quality criteria.

Methylmercury stimulates the exhalation of volatile selenium and potentiates the toxicity of selenite

The aim of the present experiments was to investigate whether a single dose of 24 μmol/kg methylmercuric chloride (MeHgCl) in rats can influence (a) the effect of an equimolar dose of sodium selenite (Na 2SeO 3) on body weight or (b) the exhalation of dimethylselenide, a volatile metabolic product of selenium. Due to the difference in their single-dose toxicities, only selenite depressed body weight gain, when given alone. The experiments indicated that methylmercury, irrespective of whether it was given 1–2 h before, or at the same time as sodium selenite, potentiated the effect of the latter on body weight. Methylmercury also increased the exhalation of volatile selenium, but this effect decreased when the administration of selenite was delayed.

Effects of selenite on O 2 consumption, glutathione oxidation and NADPH levels in isolated hepatocytes and the role of redox changes in selenite toxicity

Isolated hepatocytes incubated with selenite (30–100 μM) exhibited changes in the glutathione redox system as shown by an increase in O 2 consumption, oxidation of glutathione and loss of NADPH. Selenite (50 μM) raised O 2 consumption within the 1 h and induced an partial depletion of thiols with a concomitant increase in oxidized glutathione, as well as a decrease in NADPH levels within 2 h. With 100 μM selenite more pronounced effects were obtained such as a total depletion of thiols. This concentration of selenite also lysed cells within 3 h. Arsenite, HgCl 2 and KCN prevented the increase in O 2 uptake, counteracted loss of thiols and delayed selenite induced lysis. p-Tert-butylbenzoic acid, an inhibitor of gluconeogenesis, decreased selenite dependent O 2 consumption and potentiated the effect on NADPH levels as well as the toxic effect. Finally, methionine further enhanced O 2 consumption by selenite and also delayed loss of thiols and potentiated selenite toxicity. These results indicated that selenite catalyzed a reduction of O 2 in glutathione dependent redox cycles with NADPH as an electron donor. With subtoxic concentrations of selenite (50 μM) there were indications that O 2 reduction was terminated by selenite biotransformation to methylated metabolites. With toxic concentrations of selenite (100 μM) it appeared that O 2 reduction was eventually limited by the capacity of the cell to regenerate NADPH. It is suggested that a depletion of NADPH mediated the observed cytotoxicity of selenite.

Effect of sodium selenite on the ciliary activity, adenosine triphosphate, and protein synthesis in mouse trachea organ cultures.

Trachea from albino mice were cut transversely into nearly identical rings and incubated in medium 199 with Hanks salts and HEPES buffer at 37 degrees C. Sodium selenite at 0.5-5 mM depressed the ciliary activity. With 1 and 5 mM sodium selenite, a 50% reduction in the activity index was observed after approximately 5 and 1.5 h, respectively. The ATP content in trachea rings was reduced with 0.05-5 mM sodium selenite, and increasing concentrations gave decreasing amount of ATP after incubation for 4 and 21 h. The rate of protein synthesis as determined by incorporation of radioactive leucine was reduced with 0.5 and 2 mM sodium selenite. The synthesis was reduced quickly by 2 mM sodium selenite, which gave a 30% reduction after incubation for 1 h. It seems that the ATP levels may be used as the most sensitive indication of sodium selenite toxicity in mouse trachea.

Selenite toxicity and mercury-selenium interactions in juvenile fish.

Acute lethal toxicities of selenium and the effects of selenium on mercury accumulation were determined in freshwater fish species. Selenite concentrations required to produce 50% mortality were approximately 11 mg Se/L in northern pike (Esox lucius), 29 mg Se/L in white sucker (Catostomus commersoni), and 5 mg Se/L in yellow perch (Perca flavescens) after 75, 96, and 240 hr of exposure, respectively. Two approaches were used to determine effects of water-borne selenium on mercury concentrations in northern pike. In the first, a trend of reduced mercury contamination at a low selenium concentration (1 ug Se/L) with maintenance at control mercury contamination levels at a higher selenium concentration (100μg Se/L) was apparent. In the second, a similar response of decreased CH3 203Hg accumulation in muscle-skin at lower selenium concentrations (1 and 10μg Se/L), but maintenance at control accumulation levels at a higher selenium concentration (100μg Se/L) was observed. Results and knowledge requirements are discussed with emphasis on relevance to increasing deposition rates of these chemical elements to freshwater ecosystems and using selenium to treat mercury-contaminated aquatic systems.

Dietary Effects on Selenite Toxicity in the Chick

The toxicity of Na2SeO3 in diets containing torula (TY) or brewers’ yeast (BY) compared to a corn-soy (CS) diet was investigated. Chick mortality caused by feeding 50 or 75 ppm Se as Na2SeO3 was significantly less with TY diets than with either BY or CS diets. The TY diet was also effective in reducing the depressing effects of Se on feed consumption and weight gain. Chicks fed 50 ppm Se in the TY diet accumulated the least amounts of Se in their livers and had only moderate hepatocellular fatty metamorphosis, whereas, those fed the same level of Se in BY diet accumulated the greatest levels of Se and showed severe fatty metamorphosis. Partial or total replacement of TY (11%) with BY in the diet significantly increased mortality due to Se toxicity. Some protection against Se toxicity was associated with the ash fraction of TY. This may indicate that the protective effect of TY against Na2SeO3 toxicity is due at least in part to its mineral content.

SELENIUM: TOXICITY AND TOLERANCE IN HIGHER PLANTS

Summary1. Different plant species show considerable variation in their selenium content. Primary indicators, also termed selenium accumulators, many of which are members of the genus Astragalus, are highly tolerant of selenium; they are known to contain tissue levels of several thousand µg selenium/g. Secondary indicators, tolerant to low concentrations of the element, may absorb up to 1000 µg selenium/g. Non‐accumulators are poisoned by selenium.2. The toxicity of selenate (SeO4‐) and selenite (SeO3‐) to most plants can be attributed to a combination of three factors. Firstly, selenate and selenite are readily absorbed from the soil by roots and translocated to other parts of the plant. Secondly, metabolic reactions convert these anions into organic forms of selenium. Thirdly, the organic selenium metabolites, which act as analogues of essential sulphur compounds, interfere with cellular biochemical reactions.3. Incorporation into proteins of the amino acid analogues selenocysteine and selenomethionine, in place of the equivalent sulphur amino acids, is considered to be the underlying cause of selenium toxicity. The physical and chemical differences between selenium and sulphur will result in small, but significant, changes in the biological properties of a selenium‐substituted protein.4. Selenium‐tolerant accumulator plants differ in at least two respects from sensitive species. Large quantities of Se‐methylselenocysteine and selenocystathionine, two non‐protein selenoamino acids rarely detected in non‐accumulators, have been isolated from the tissues of selenium accumulators. In addition, selenium is kept from entering proteins so that the selenium levels in proteins of accumulator plants is significantly lower than the levels in selenium‐sensitive plants.5. Exclusion of selenium from the proteins of accumulators is thought to be the basis of selenium tolerance. Discrimination against selenocysteine during protein synthesis seems to prevent incorporation of this selenoamino acid into proteins of accumulators. Furthermore, synthesis of Se‐methylselenocysteine and selenocystathionine, which results in diversion of selenium away from the synthesis of selenomethionine, will restrict the amount of this compound available for protein synthesis.6. Selenium accumulation among unrelated plant genera is a striking example of convergent evolution. The possibility that accumulation of this element is associated with a nutritional requirement for selenium, although explored in the past, is still in need of further clarification.

Metabolism of toxic substances in isolated hepatocytes

Chloroform and selenite toxicity have been studied in isolated hepatocytes. Two different toxic mechanisms, which lead to cellular lysis after distinct lag periods, are compared. Chloroform toxicity can be divided into 2 phases, a first phase characterized by chloroform metabolism and a second phase characterized by lipid peroxidation. GSH depletion during the first phase is claimed to be a prerequisite for lipid peroxidation in the second phase. Selenite metabolism leads to cofactor depletion as well. Selenite reduction via a GSH reductase dependent pathway exhausts the cells of NADPH and this effect can be related to cellular lysis.

A tissue culture model for mercury-selenium interactions

In five- and six-day growth studies, Chang's liver cells and 3T3 cells were protected against selenite toxicity by mercuric chloride and by monomethyl mercury. They were also protected against mercuric chloride toxicity by selenite. The following results were obtained with Chang's liver cells only: Methyl mercury inhibits selenite uptake, and the optimal molar ratio of Ch 3HgCl to Na 2SeO 3 in the medium is on the order of one-tenth. These two observations suggest that methyl mercury interferes with sites for selenite transport into the cell. The optimal HgCl 2 Na 2 SeO 3 molar ratio in the growth medium varies from 1.2 to 2.0. At protective levels, selenite increases uptake of mercuric chloride on a per-cell basis. The molar ratio of uptake of the two substances varies with their ratio in the medium, but not in a linear fashion. These results suggest a minimum of two different protective interactions between mercuric chloride and sodium selenite.

Selenite toxicity, depletion of liver S-adenosylmethionine, and inactivation of methionine adenosyltransferase

The possibility that dimethyl selenide production depletes liver S-adenosylmethionine was explored as a biochemical basis for selenite toxicity. Toxic doses of selenite (25 nmol/ g body weight) were found to rapidly decrease mouse liver S-adenosylmethionine and increase S-adenosylhomocysteine, indicative of an increased rate of transmethylation. However, S-adenosylmethionine levels remained depressed beyond the time when dimethyl selenide synthesis ceased, suggesting that selenite inactivated methionine adenosyltransferase. This was found to be the case in vivo by measuring the effect of graded doses of selenite on the conversion of the methionine analog, ethionine, to S-adenosylethionine. In vitro studies also indicated inactivation of this enzyme by selenite. Liver homogenates from mice injected with 25 nmol of selenite/g, as above, were found to have less than 50% of the methionine adenosyltransferase activity of saline-injected controls.

Development of hemolytic anemia in rats fed selenite

The anemia of selenite toxicity in rats was studied with 59Fe. When the 59Fe was injected into control animals and into selenite-fed animals which would soon show anemia, the uptake of radioactivity in the blood was the same. In observing the fatal anemia that then developed with the selenite-fed animal, an extensive decline of the hemoglobin concentration and of the newly incorporated 59Fe in the blood occurred at the same time. An interruption of the decline might occur. At death, the overall reduction of the hemoglobin concentration in the blood was less than the reduction of the label. During the terminal stage, hemoglobinuria occurred. The animals which did not show extensive loss of the 59Fe in the blood also did not show anemia or die. The results indicated that the anemia was caused by hemolysis rather than by a defect in red blood cell synthesis. The effect of the selenite treatment on the 59Fe loss from the blood was reduced when arsenite was included in the diet. The use of arsenite in the diet without selenite also appeared to have some sparing effect on the 59Fe loss. When arsenite was fed with labeled selenite, a reduction in the selenium level in the liver and kidneys occurred. Thus, arsenite addition to a selenite-treated diet was associated with a reduction in hemolysis and in selenium accumulation in certain organs.

Absence of effect of tocopherol on acute oral toxicity of sodium selenite in the rat.

SummaryThe acute oral toxicity of sele-nite-selenium in the rat is approximately LD50, 12.5 mg/kg; this level is not changed by simultaneous administration of tocopherol as d-α-tocopherol acetate at 725 mg/kg.