Jadwiga A. Szymańska

Hepatotoxicity of tetrabromobisphenol-A: effects of repeated dosage in rats.

Tetrabromobisphenol-A (TBBP-A) is used as a reactive flame retardant and as an intermediate in the production of other flame-retardants. In our study, TBBP-A was administered intragastrically, daily for 7 or 7-28 days at three dose levels. Significant changes of biochemical indicators were noted with regard to glutathione (GSH), malondialdehyde (MDA) and 5-aminolevulinate dehydratase (ALA-D). The level of GSH was lowered by the two higher doses (female rats only) and MDA was elevated by the highest dose (male rats only). The ALA-D activity reacted in opposite directions for both sexes. Other indicators did not yield any conclusive results. The 28-day study was performed on female rats. For GSH and MDA the medium dose resulted in a systematic increase. Insignificant changes in ALA-D activity in the liver were observed throughout the experiment. The activity of 5-aminolevulinate synthase had a decreasing tendency at 250 mg/kg of TBBP-A during the whole time of observation. Other general indices such as the activity of gamma-glutamyltransferase, concentration of microsomal proteins and the level of cytochrome P-450 did not show any significant changes. The most pronounced changes were noted with regard to indicators of porphyrogenic action. The results suggest that TBBP-A is capable of disturbing the heme metabolism in rats.

The disposition and metabolism of tetrabromobisphenol-A after a single i.p. dose in the rat

Tetrabromobisphenol-A (TBBP-A) is used as a reactive (primary use) or an additive flame retardant and as an intermediate in the production of other flame retardants. In our study TBBP-A[14C] was administered intraperitoneally (i.p.) in a single dose of 250 or 1000 mg/kg body weight (about 300 kBq per animal). The level of radioactivity in erythrocytes was 10 times higher than in plasma 72 h after the administration. In all examined tissues the peak level of 14C could be observed within the first hour after the administration, and the highest concentrations were detected in the fat tissue, followed by liver, sciatic nerve, muscles and adrenals. Total excretion in faeces 72 h after the administration was about 51-65% of the dose, whereas in urine it was only 0.3%. About 20% was still retained in the rat organism.

Hepatotoxicity of brominated benzenes: relationship between chemical structure and hepatotoxic effects in acute intoxication of mice

Abstract Brominated benzenes appear in the environment and human tissues. Their detection in the environment may be as a result of their usage, e.g. hexabromobenzene (HBB), and as products of HBB degradation or metabolism. The aim of this study was to compare liver impairment in acute intoxication of mice with bromobenzene (BB), 1,2,4-tribromobenzene (1,2, 4-triBB), 1,3,5-tribromobenzene (1,3,5-triBB), 1,2,4,5-tetrabromobenzene (1,2,4,5-tetraBB) and hexabromobenzene (HBB). The data for these compounds were compared with the data obtained for dibromobenzenes (1,2-dBB, 1,3-dBB, 1,4-dBB). Male Balbc mice were administered the investigated compounds in single, intraperitoneal doses equal to 20–90% of the approximate lethal dose (ALD). Acute toxicity of bromobenzenes decreases with the increase of the number of bromine atoms in the molecule. All examined compounds decreased the liver glutathione (GSH) level in a short time following administration. Later in the experiment, GSH either returned to control values or the concentration increased. Changes in alanine aminotransferase (ALT) activity in mice serum depended on the type of compound and the time of observation. BB, 1,2-dBB, 1,3-dBB and 1,2,4-triBB caused statistically significant increases (30- to 120-fold) in ALT activity. For the remaining compounds these changes were not significant being two- to threefold. Histopathological examination demonstrated that BB, 1,2-dBB, 1,3-dBB and 1,2,4-triBB resulted in coagulative or haemorrhagic necrosis in the liver central lobular zone. All investigated compounds resulted in the increase of gamma-glutamyltransferase activity in serum and malondialdehyde concentration in liver. Octanol water partition coefficient (expressed as log P) and molecular volume (log V) were calculated for all examined compounds. With the increase of lipophilicity and molecule size, the ability of the examined compounds to decrease the level of GSH in mice liver and increase ALT activity in the serum diminishes.

Distribution of tin in the rat and disturbances in the metabolism of zinc and copper due to repeated exposure to SnCl2

The effect of stannous chloride on tissue concentrations of zinc and copper was studied in female rats. The animals were subjected to repeated exposure to seven doses given every other day 2 mg Sn/kg, subcutaneously. About 60% of tin 113Sn was retained in the body. Of this amount, about 95% accumulated in the skin and hair. In the remaining organs the tin concentrations corresponded to 2.57 to 0.0001% of the retained dose. In comparison with the control group a 3-fold increase of the content of zinc was found in the liver while a decrease were revealed in the spleen, heart, brain, lungs, and especially in muscle. A statistically significant decrease of the copper content was found in the blood and brain.

Effect of selenium on the organ distribution and binding of bismuth in rat tissues.

Subcutaneous administration of bismuth, both single and multiple, resulted in deposition of this metal mainly in the kidneys which contained over 50% of the ‘accessible pool’ of bismuth. In the kidneys bismuth was bound mainly by the soluble fraction in which it was complexed with a protein of molecular weight of about 7000. Multiple administration of bismuth increased the level of this protein. Selenite administration brought about an increase in the ‘accessible pool’ of bismuth, probably due to a drop in excretion, and also changes in the organ distribution of this metal. The retention in the kidneys was diminished while those in the liver and in other tissues were augmented. These changes were accompanied by a change in the chemical form of bismuth present in the kidneys manifested by the total disappearance of the protein complex of molecular weight of 7000. The increased synthesis of this protein due to bismuth administration was not abolished completely.ZusammenfassungNach einmaliger und wiederholter subkutaner Verabreichung wurde Wismut zu mehr als 50% der „erreichbaren Menge” in den Nieren gefunden. Es war dort vorwiegend in der löslichen Frakion und in großem Umfang an einen Eiweißstoff vom Molekulargewicht 7000 gebunden. Bei wiederholter erabreichung von Wismut wurde auch dieser Eiweißstoff vermehrt gefunden. Die gleichzeitige Verabreichung von Selen erhöhte die „verfügbare Menge” von Wismut, wahrscheinlich wegen eingeschränkter Ausscheidung. Zugleich wurden Unterschiede in der Organverteilung von Wismut festgestellt. Der Anteil in den Nieren wirde geringer und derjenige in Leber und sonstigen. Organen größer. Der Eiweißkomplex mit dem Molekulargewicht 7000 verschwand gänzlich. Die durch Wismut stimulierte Synthese dieses Eiweißstoffes wirde aber nicht ganz verhindert.

Acute and subacute nephrotoxicity of 2-bromophenol in rats.

The present report aims at providing broader information on the acute nephrotoxicity of 2-bromophenol (2-BP) (a bromobenzene (BB) metabolite), due to its action on the kidneys, after repeated administration. Investigations were performed on female rats. Following a single dose, the most pronounced changes involved: concentrations and rates of excretion of proteins in urine, the number of epithelial cells excreted in urine, creatinine and urea clearance and reduced glutathione in renal tissue. Immediate effects could be ascribed to both renal tubules and glomeruli, mirrored in the level of urinary proteins and intensified excretion of renal epithelial cells. Less pronounced changes of the indicator values were noted under repeated dosing of 2-BP. The results obtained in a single exposure study confirm earlier reports on the mild nephrotoxicity of 2-BP following exposure to high doses. However, the transition from single to repeated exposure does not result in enhanced nephrotoxicity.

Hepatotoxicity of monobromobenzene and hexabromobenzene: effects of repeated dosage in rats

The aim of the study was to determine whether monobromobenzene (BB) and hexabromobenzene (HBB) administered repeatedly (for 28 days) to female rats resulted in disturbances of heme synthesis. 5-Aminolevulinate dehydratase (ALA-D) and 5-aminolevulinate synthase (ALA-S) activities were slightly changed and the concentration of glutathione increased. The excretion of 5-aminolevulinic acid (ALA-U) in urine after all doses of BB and HBB increased already in the first week. After BB administration, increased excretion of coproporphyrins was detected only at the highest dose. The increased excretion of coproporphyrins following the administration of HBB could be observed already at the lowest dose (15 mg/kg). The excretion of uroporphyrins increased after two higher doses (75 and 375 mg/kg) in the fourth week of exposure. HBB also caused elevation of microsomal P450 level. The data suggest porphyrogenic activity of HBB; whereas in the case of BB we cannot exclude that elevated excretion of ALA-U resulted from kidney impairment.

Biochemical alterations as measures of acute and subacute hepatotoxicity of 1,3-dibromobenzene in rat

Abstract Rats were used to study acute and subacute hepatotoxicity of 1,3-dibromobenzene (1,3-dBB). In the single-exposure experiment, maximum hepatic 1,3-dBB concentrations were found to occur 1 to 12 h after the exposure, depending on the dose. Maximum concentrations of covalently bound adducts were reached after 12 h. Depletion of hepatic glutathione (GSH) content occurred during the first 24 h following the exposure, but was not accompanied by changes in alanine aminotransferase (ALT) activity. The increased number of doses also did not result in necrotic lesions of the liver. In the subacute (28-day) experiment, higher hepatic GSH levels and increased blood serum gamma-glutamyltransferase (γ-GT) activity were observed. Exposure to 1,3-dBB resulted in increased porphyrin excretion in urine, without accompanying increase in the removal of delta-aminolevulinic acid (AlA-U). The results indicate that subacute exposure to 1,3-dBB produces porphyrinuria in the rat.

The effect of short-term intoxication of rats with pentabromodiphenyl ether (in mixture mimic commercial products)

Until quite recently, pentabromodiphenyl ether (PentaBDE) was most commonly used as a flame retardant. Due to the considerably long atmospheric half-life of PentaBDE and its contribution to environmental pollution, it is categorized as a persistent organic pollutant (POP). As the data on the toxicity of PentaBDE is rather scarce, its potential acute toxicity was the subject of this study. PentaBDE was administered intragastrically to female rats, in a single dose (25, 200 or 2000 mg/kg b.w.). PentaBDE administered to rats disturbed redox homeostasis, which was manifested by lower total antioxidant status (TAS) in serum and by higher liver glutathione reduced (GSH) concentration. The toxic effect of PentaBDE intensified lipid peroxidation. On histopathological examination, administration of the highest PentaBDE dose (2000 mg/kg b.w.) was seen to induce symptoms of fatty liver. PentaBDE caused an increase in relative liver mass, cytochromes P-450 (after two highest doses), a dose-dependent increase in the activity of CYP lA (12—26 fold) and CYP 2B (5—6 fold) as well as the levels of CYP lAl (16—50 fold) and CYP 4A (2—3 fold) in liver.

Octabromodiphenyl ether — porphyrogenicity after repeated administration to rats

ObjectivesOctabromodiphenyl ether (OctaBDE) is a flame retardant which has been withdrawn from common use due to its negative effect on the environment. The literature data regarding its toxicity addresses its effect on liver function, the endocrine and reproductive systems, as well as its developmental toxicology aspects. The aim of this study was to investigate the effect of repeated administration of OctaBDE on heme biosynthesis in rats.Materials and MethodsThe study was performed on female Wistar rats. OctaBDE was administered intragastrically at four different doses (2, 8, 40 or 200 mg/kg/day) for 7, 14, 21 or 28 days. The following measures of heme synthesis disturbance were used: urinary excretion of porphyrins, liver concentration of porphyrins, the activity of delta-aminolevulinate synthase (ALA-S) and delta-aminolevulinate dehydratase (ALA-D) in the liver.ResultsAfter 28 days of exposure, lower ALA-S and ALA-D activity was observed in the liver. Additionally, increased concentrations of high carboxylated porphyrins (octa- and heptacarboxyporphyrins) were found in the liver: from 2- to 10-fold after the 2 mg/kg/day doses and from 4- to 14-fold after the 8-200 mg/kg/day doses. The porphyrogenic effect of OctaBDE was also evidenced by augmented, dose-dependent and exposure time-dependent, concentrations of total porphyrins in urine (2–7.5-fold increase) and their urinary excretion (2-9-fold increase). Tetracarboxyporphyrins predominated in the urine; their concentrations increased 2.5–10 fold. Conclusions: The study revealed that repeated exposure to OctaBDE affects heme biosynthesis and the levels of porphyrins. The lowest effective level which induced changes in porphyrin concentration was 2 mg/kg/day.