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 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.

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 1,3-dibromobenzene in the rat.

The distribution, excretion and metabolism of 1,3-dibromobenzene following a single i.p. administration to rats 100 or 300 mg/kg was investigated using radiotracer [3H] and GC-MS technique. After 72 hours about 74 to 90% were excreted in urine. The highest radioactivity was observed in the liver, kidneys and fat tissue. Later on a steady decline of radioactivity was apparent in all investigated tissues except for blood cells and the sciatic nerve, where constant levels were noted. In urine the following substances were identified and quantified by GC peak areas: unchanged 1,3-DBB (18%), dibromophenols (34%), dibromothiophenols (28%), dibromothioanisole (1.8%), bromophenol (5.5%), bromohydroxythiophenols (5%), and bromohydroxythioanisole (7.5%).

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

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.

The distribution and excretion of hexabromobenzene after a single administration in rat.

The aim of this study was to investigate the disposition of [1-14C]-hexabromobenzene (HBB) in rats. The experiments were performed on 76 female Outbred IMP: Wist rats with body weight of 200 g +/- 20%. The compound was given orally in a single dose of 600 mg/kg and 4500 mg/kg. 14C radioactivity was traced in selected tissues, blood, urine and faeces, 0-72 hours following the administration. Maximum concentration of the 14C in blood was observed during the 2nd hour after the compound administration. The accretion of 14C in plasma proceeded with kinetic constant of 1.35/hour, whereas 14C-decline was biphasic. Half-lives for phase I and II were 1.2- and 440 hours, respectively. No substantial differences were noted in relation to the HBB dose. In tissues the highest radioactivity was observed in the fat tissue, adrenals and sciatic nerve. About 16 to 24% of the administered radioactivity was still retained in the rat body, 72 hours after administration of the compound. Faeces turned out to be the main route of excretion (about 75% of the given dose); only 1% was excreted in urine. Following on the literature data and our total balance of 14C elimination with faeces, we concluded, that almost 70% of 14C found in the faeces were composed of other metabolites than HBB and its lower-brominated derivatives. The above data indicate that HBB, especially in the case of chronic exposure, might accumulate in the body.

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

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 (gamma-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.

[Toxicity of selected brominated aromatic compounds]. / Toksykologia wybranych bromopochodnych aromatycznych.

Flame retardants are added to plastic materials, textiles, wood, hydraulic liquids etc. for reducing their inflammability. These substances reduce the heat and carbon monoxide formation in case of fire. They are added in high amounts, even up to 30% of product mass (e.g. plastic material). The production of brominated flame retardants has been steadily rising in the last 20 years, e.g. in the 1990s the world production of polybromodiphenyl ethers (PBDE) reached 40,000 tons annually. Mainly polybrominated flame retardants are produced, e.g. polybromobiphenyls (PBB), PBDE, hexabromobenzene (HBB). Their toxicity is low or nil, the DL 50 values are over 1 g/kg. However, when administered in low doses over longer time periods they can cause changes leading to porphyria. The information on the toxicity of polybrominated flame retardants for humans is derived mainly from the accident in Michigan, where PBB contamination of fodder for farm animals occurred with consequent contamination of food. In consumers of contaminated food cutaneous changes and neurological and muscular symptoms were noted. Polybrominated flame retardants can be metabolized and undergo biodegradation mainly trough debromination. The data on the toxicity of debromination products point to di- and tribromobenzenes, some of which are highly hepatotoxic. In acute poisoning hepatocellular damage manifest itself as necrotic changes in experimental animals receiving 0.1-0.8 of DL 50 of di- or tribromobenzene. After repeated administration of lower doses the hepatocellular damage assumes the features of porphyrogenic injury. In the environment polybrominated flame retardants can be transformed by various factors (high temperature during fire accidents, incomplete incineration of waste) to polybrominated dibenzodioxins of dibenzofurans whose lethal doses can in extreme cases be 0.001 mg for 1 kg body weight.

Comparison of hepatotoxicity of 1,2-, 1,3- and 1,4-dibromobenzenes: the dynamics of changes of selected parameters of liver necrosis in acute poisoning in mice.

Various doses of dibromobenzene isomers (1,2-dBB, 1,3-dBB, 1,4-dBB) were administered (i.p.) to BALB mice. The levels of reduced glutathione (GSH) and malondialdehyde (MDA) in the liver, and glutamate-pyruvate transaminase (GPT) (EC.2.6.1.2) gamma-glutamyltransferase (gamma-GT) (EC.2.3.2.2) and triglycerides (TG) in the serum were estimated. A considerable decrease of GSH was observed between 2 and 12 h after administration of the compounds. Increases in serum GPT activity (up to 100-fold) and gamma-GT (three-to fivefold) were observed after treatment using 1,2- and 1,3-dibromobenzenes; TG decreased in concentration initially and then slightly increased. Histopathological examination confirmed the strong necrotic effect of 1,2- and 1,3-dBB isomers. No such changes (elevation of serum GPT activity and necrosis) were noticed after 1,4-dBB.

Investigations on acute hepato- and nephrotoxicity of pentabromophenol.

Pentabromophenol (PBP) was administered in a single or repeated doses to mice or in a single dose to rats. Slight changes were noted in the level of SGPT in mice serum and GSH in the liver, with a more pronounced increase of MDA after a single dose. Following repeated administration, gamma-GT and MDA were elevated. The nephrotoxic action of PBP in rats was manifested by the decreased of renal GSH levels, as well as by an increase in protein contents and the number of renal epithelial cells in urine. As a result, limited hepatotoxicity was found only in mice. The nephrotoxicity in rats was comparable with that for 2-bromophenol described earlier.

Influence of bismuth on the metabolism of endogenous metals in rats.

In this study the effect of single and multiple doses of bismuth on the metabolism and excretion of endogenous metals (Cu, Zn) was investigated. Wistar rats were administered bismuth chloride subcutaneously (1 x 3 mg Bi/kg or 7 x 3 mg Bi/kg). Rats were sacrificed at different time periods after bismuth injections. The levels of Cu and Zn were determined in the liver, kidneys and brain, as well as the concentrations of metallothionein (MT) in the liver and kidneys. Cu, Zn and total protein levels in the urine of control and exposed animals were estimated. Additionally, a histopathological examination of the kidneys and brain was carried out. The increase in the renal and hepatic Cu and Zn content was paralleled by an augmentation in the level of MT in these organs following both kinds of exposure to bismuth. Some changes in the ultrastructure of the kidneys were correlated with the dose of bismuth. Zinc content in the brains of exposed rats was lower than in control animals brains, but there was no difference in copper level and no histological changes. The excretion of copper and zinc was higher in the exposed groups than in control groups. The presented results indicate that the disturbances in the metabolism of Zn or Cu in the liver, kidneys and brain and the increase in urinary output of metals may be a much more sensitive index than morphological damage and impaired renal function to the bismuth exposure.

Effects of 3-methylcholanthrene or diethyl maleate on the hepatotoxicity of acetaminophen.

This report presents a set of investigations on the hepatotoxic action of acetaminophen (AA). Male mice of Balb C strain were given [3H]acetaminophen in doses of 100, 300 and 600 mg kg-1 with or without pretreatment with 3-methylcholanthrene (3MCh) or diethyl maleate (DEM). The results of this study show that AA administered in moderate doses brings about necrotic changes due to adduct formation with macromolecules. Adduct formation was inversely correlated with the level of glutathione. Both modifiers enhanced hepatic necrosis and lethality. Diethyl maleate exerted these effects without enhancing covalent binding to macromolecules, while 3MCh increased both adduct formation and lipid peroxidation.

Changes in concentration of essential metals in kidneys and urine as indices of gentamicin nephrotoxicity in female Wistar rats.

Wistar rats were treated with gentamicin in single (80 mg/kg) or repeated doses (7 x 40 mg/kg) subcutaneously. Total protein as well as excretion of essential metals (Cu, Zn) with the urine were determined 24 hr after 1, 3 and 7 dosages as well as 3 and 7 days after the termination of administration. At the same time kidneys were examined histopathologically by light microscopy. Simultaneously, Cu, Zn and metallothionein levels in kidneys and liver were determined. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis at the end of 7 days administration. At the same time elevated copper and zinc levels were observed in urine. These essential metals seem to be an indicator of gentamicin nephrotoxicity.

Intestinal absorption of inorganic mercury in rat.

203Hg-Mercuric chloride was administered intragastrically to female rats. The absorption rate evaluated for a broad range of doses was found constant for low and medium range, and higher for high doses. Mercury was determined in internal organs and intestines. The time-course of intestinal mercury indicated that a deposit formed initially in the mucosa was further absorbed into the circulation. No indication was found of a protection mechanism based on exfoliation of the mucosal deposits of metal.

Protective effect of zinc in the hepatotoxicity of bromobenzene and acetaminophen.

Mice of the Balb'c strain were administered bromobenzene (BB) or acetaminophen (AA) i.p., in single doses of 400 and 300 mg/kg, respectively. In the blood activity of SGOT and SGPT as well as SDH was determined. In the liver the level of metallothionein (MT), malondialdehyde (MDA) and glutathione (GSH) was measured. The level of MT as well as GSH (determined as non-protein SH groups) showed a significant increase following administration of zinc alone. Joint action of zinc and either BB or AA resulted in a decrease of GSH which was less pronounced than expected for each of the xenobiotics alone. The protective effect of zinc reflected in the reduction of the increase of SGPT and SGOT activity was apparent shortly (4 h) after administration of AA. A day after injection of AA alone the activity of enzymes was lower and the rate of decline followed the sequence SGPT greater than SGOT greater than SDH. For BB, both the toxic effect and the protective influence of zinc were apparent 24 h following administration. At 4 h in a group receiving BB alone no changes of the indicatory enzymes in blood were noted.

[Health effects of exposure of humans to inorganic arsenic compounds]. / Skutki zdrowotne narazenia ludzi na nieorganiczne zwiazki arsenu.

This paper is a review of references concerning health effects of environmental and occupational exposure to inorganic arsenic compounds. Special attention is paid to epidemiological studies indicating a relationship between time and amount of arsenic absorbed via the gastrointestinal tract (drinking water, contaminated food, drugs) and an increase in skin cancer rate. Occupational and environmental exposure of humans to arsenic dust induces a higher risk of lung cancer.

Renal binding of cadmium in the rat following intragastric exposure.

Renal binding of cadmium was compared in groups of rats administered cadmium intragastrically or subcutaneously in doses resulting in similar renal cadmium concentrations. In rats administered cadmium intragastrically the renal concentrations of copper and metallothionein were lower, suggesting disturbance in copper metabolism. These changes were alleviated gradually in the post-exposure period. In experiments with 64Cu it has been shown that intragastric exposure to cadmium reduced copper absorption to about 21% of that in the control rats, thus explaining the poor copper availability for renal binding of cadmium in the form of Cd,Cu-metallothionein. Changes in zinc uptake were less strongly marked and were limited to slight decrease of zinc content in the kidneys.

Intestinal absorption of cadmium and inorganic mercury in the rat: no major involvement of metallothionein.

The intestinal absorption of cadmium and inorganic mercury was studied in adult rats, administered the metal salts intragastrically or parenterally in repeated or single doses. The intestines contained only small proportion of the body burden; no major change was found in the intestinal level of metallothionein, copper and zinc. Therefore, no major role can be ascribed to intestinal metallothionein in limiting absorption of high oral doses of cadmium and mercury.

Spectroscopic properties of the alpha fragment of metallothionein.

Absorption, CD, and magnetic circular dichroism spectra are reported for the alpha fragment of rat liver Cd,Zn-metallothionein (MT) 2. The CD and magnetic circular dichroism spectra of the Cd4 cluster unit are particularly well-resolved and are remarkably similar to data of the complete Cd,Zn-MT. It is suggested that the high signal intensity in the 225 nm CD band may be attributed to an interaction between a terminal amino acid residue and the Cd4 cluster. Titration experiments with CdCl2 and [Cu(CH3CN)4]+ show that while no additional Cd2+ can be bound in the presence of excess Cd2+, Cu+ does replace the bound Cd2+ in a complex reaction to form at least two species. One of these species requires the presence of both Cu+ and Cd2+, with a stoichiometry of Cu 3.0, Cd 2.5. Further, Cu+ displaces all the remaining Cd2+, and the spectra recorded now closely resemble Cu-MT formed by titration of Cd,Zn-MT with greater than 8 mol eq of Cu+.