Commercial Mixture Of Polybrominated Biphenyls Research Articles

Development of preneoplastic lesions in the liver and nasal epithelium of rats initiated with N-nitrosodimethylamine or N-nitrosopyrrolidine and promoted with polybrominated biphenyls

In rats, N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) induce liver tumours and, to a lesser extent, nasal tumours. Polybrominated biphenyls (PBBs) are liver tumour promoters and are highly persistent in tissues of rats. To characterize the development of preneoplastic lesions in the liver and nasal cavity, female Sprague-Dawley rats were initiated with NDMA or NPYR and promoted with Firemaster (FM), a commercial mixture of PBBs. Rats were killed after 30, 120 or 180 days of promotion. Liver and nasal tissues were stained with haematoxylin and eosin and were tested immunohistochemically for glutathione S-transferase placental form (GST-P). Significantly more altered hepatocellular foci (AHF) were evident in rats initiated with NDMA or NPYR and promoted with FM compared with non-promoted groups or rats given only FM. Appreciable numbers of AHF were seen at 120 and 180 days in livers of rats in all other treatment groups, whereas the untreated control rats had no AHF. The percentage volume of the liver occupied by AHF was significantly higher in promoted rats given NDMA than in rats given only NDMA or FM. These results indicate that a single oral dose of PBB can significantly enhance development of AHF in rats initiated with NDMA or NPYR. Preneoplastic lesions in nasal tissues were not detected by staining with GST-P.

Short-term oral administration of polybrominated biphenyls enhances the development of hepatic enzyme-altered foci in initiated rats.

FireMaster BP-6 (FM), a commercial mixture of polybrominated biphenyls (PBB), has been shown to act as a tumor promoter in hepatocarcinogenesis assays in rats. Most hepatic tumor promoters must be administered for many weeks or months. Because FM is highly persistent in animal tissues, it was hypothesized that very short-term administration of FM would result in tumor promotion. Female Sprague-Dawley rats weighing 185-215 g were initiated by a two-thirds partial hepatectomy followed by 10 mg diethylnitrosamine/kg body weight (BW) 24 h later. Thirty days later, rats were gavaged with FM in corn oil, at total doses of 0, 13, or 130 mg FM/kg BW. Half the dose was given on d 30, and the remaining half was given 24 h later. At 120 d after gavage the rats were killed and necropsied. Five liver sections from each animal were histochemically stained for gamma-glutamyl transpeptidase-positive enzyme-altered foci (EAF). EAF were significantly increased over control values in initiated rats given 130 mg FM/kg. In animals given 13 mg FM/kg, EAF were increased to a lesser extent but not significantly above controls. Enhancement of these EAF in initiated rats reflects tumor-promoting activity. In this study, 24-h administration of FM in initiated rats was sufficient to enhance hepatic EAF measured 120 d later in an rats was sufficient to enhance hepatic EAF measured 120 d later in an initiation-promotion protocol, and a dose of 13 mg FM/kg was apparently close to a possible no-effect threshold level for enhancement of EAF.

Procedures to enhance withdrawal of xenobiotics from chickens.

Egg- and meat-type chickens were fed diets containing 1 or 10 ppm of fireMaster (FF-1), a commercial mixture of polybrominated biphenyls (PBBs), predominantly 2,4,5,2',4',5'-hexabromobiphenyl (6BB-4) and 2,3,4,5,2',4',5'-heptabromobiphenyl (7BB-8). These congeners account for approximately 65 and 14%, respectively, of the total mix. In three experiments, colestipol hydrochloride, a bile acid-binding resin, and mineral oil, alone or in combination with restricted feeding, were examined as procedures to enhance the removal of the PBBs. The combination of 50% dietary restriction plus a 10% dietary concentration of colestipol or mineral oil reduced body burdens of PBBs about 70% within 21 d for chickens previously fed 10 ppm PBBs. The use of feed restriction, colestipol, or mineral oil produced only borderline effects for hastening withdrawal. Chickens not treated showed only a 3% loss of PBBs during the withdrawal period. Colestipol at 2.5% in the diet in combination with feed restriction was not consistently effective in removing body burdens of PBB from chickens previously fed 1 or 10 ppm PBBs, indicating a dose-response effect. Chickens previously fed 1 ppm eliminated up to 40% of the PBBs in 21 d without any treatment, as compared to the 3% loss occurring after feeding with 10-ppm concentrations.

Effect of varying the length of exposure to polybrominated biphenyls on the development of gamma-glutamyl transpeptidase enzyme-altered foci.

Female Sprague-Dawley rats were fed polybrominated biphenyls (PBBs) for 15 or 140 days after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine the effect of varying the length of exposure to PBBs on the enhancement of gamma-glutamyl transpeptidase enzyme-altered foci. fireMaster BP-6R, a commercial mixture of PBBs, was fed to rats at a dietary concentration of 100 mg/kg for 15 days or 10 mg/kg for 140 days during the promotion phase of a two-stage hepatocarcinogenesis assay. Results indicate that short term exposure to PBBs is as effective as long term exposure in enhancing the development of enzyme-altered foci.

Polybrominated biphenyls as aryl hydrocarbon hydroxylase inducers: structure-activity correlations

The synthesis of all possible laterally-substituted polybrominated biphenyl (PBB) congeners containing two para bromines is described. Using enzymic, electrophoretic and ligand-binding assays that distinguish between phenobarbitone(PB)- and 3-methylcholanthrene(MC)-type inducers, the synthetic PBBs were evaluated as inducers of liver microsomal drug-metabolizing enzymes in the immature male Wistar rat. 4,4′-Dibromobiphenyl resembled PB in its mode of induction whereas all the meta-brominated derivatives of 4,4′-dibromobiphenyl, namely 3,4,4′-tri-, 3,4,4′,5-tetra-, 3,3′, 4,4′-tetra-, 3,3′,4,4′,5-penta- and 3,3′,4,4′,5,5′-hexabromobiphenyl, resembled MC in their mode of induction. The results obtained with 3,4,4′-tribromobiphenyl demonstrate that, in contrast to the polychlorinated biphenyls (PCBs), a single meta halogen substituent is sufficient to abolish the PB-type characteristics of 4,4′-dibromobiphenyl and convert it to a strictly MC-type inducer. PBBs which induce AHH activity must be substituted at both para positions and at one, two, three or four meta positions. Ortho-substitution of PBBs which contain only lateral bromine groups may also give compounds which are aryl hydrocarbon hydroxylase (AHH) inducers. One of the MC-type PBBs, namely 3,3′,4,4′-tetrabromobiphenyl, which has been tentatively identified in the commercial PBB mixture, fireMaster BP-6, was at least 50 times more potentias an inducer of AHH activity than the commercial PBB mixture. The induction of AHH by 3,3′,4,4′-tetrabromobiphenyl was accompanied by a dose-dependent decrease in both thymus and spleen weights. The thymus and/or spleen weights were decreased in rats treated with the other MC-type PBBs which further supports the correlation between the toxicity of the PBBs and their ability to induce AHH.

Pathologic Effects of 2,2 prime ,4,4 prime ,5,5 prime - and 2,3 prime ,4,4 prime ,5,5 prime -Hexabromobiphenyl in White Leghorn Cockerels

Pathologic effects of 2,2',4,4',5,5'-hexabromobiphenyl (HBB), 2,3',4,4',5,5'-HBB, and a commercial mixture of polybrominated biphenyls (PBB) were compared in White leghorn cockerels. Diets containing 1, 10, or 100 ppm PBB, 4 or 10 ppm 2,3',4'4',5,5'-HBB, or 10 or 62 ppm 2,2',4,4',5,5'-HBB were fed for 28 days. Doses of 10 ppm of each chemical were used to provide a direct comparison of toxicity. Since nearly 4% of PBB consists of 2,3',4,4',5,5'-HBB and approximately 62% consists of 2,2',4,4',5,5'-HBB, effects of doses of 4 and 62 ppm, respectively, were compared with effects of 100 ppm of PBB to determine if either of the congeners were mainly responsible for the pathologic effects caused by the mixture. Liver weights were increased in cockerels fed diets containing 62 ppm of 2,2',4,4',5,5'-HBB or 10 or 100 ppm PBB. Hepatocytes were enlarged and vacuolated and lymphoid cells of the bursa of Fabricius were depleted by 10 ppm 2,3',4,4',5,5'-HBB, ppm 2,2',4,4',5,5'-HBB, and 10 or 100 ppm PBB. These dietary concentrations caused ultrastructural changes in hepatocytes consisting of vacuolation, increased smooth endoplasmic reticulum, swollen mitochondria, and disruption of mitochondrial cristae. When either of the congeners were given in concentrations relative to their concentrations in PBB, they were less toxic than the mixture. When concentrations in diets were equal, PBB caused more severe effects than 2,3',4,4',5,5'-HBB. The least effects were seen with 2,2',4,4',5,5'-HBB. Results indicate that the two congeners chosen for study are not individually as toxic as the parent mixture.

Acute pathologic effects of 3,3′,4,4′,5,5′-hexabromobiphenyl in rats: Comparison of its effects with Firemaster BP-6 and 2,2′,4,4′,5,5′-hexabromobiphenyl

Male Sprague-Dawley rats were fed diets containing 0, 0.1, 1, 10, or 100 ppm of 3,3′,4,4′,5,5′-hexabromobiphenyl (HBB), 2,2′,4,4′,5,5′-HBB, or Firemaster (FM) BP-6, a commercial mixture of polybrominated biphenyls, for 9 days. Although 3,3′,4,4′,5,5′-HBB is not in FM BP-6, it was used because it is a 3-methylcholanthrene (MC)-type inducer of hepatic drug-metabolizing enzymes. Nearly one-half of FM BP-6 is comprised of 2,2′,4,4′,5,5′-HBB and this congener is strictly a phenobarbital (PB)-type inducer. FM BP-6 has both MC- and PB-type induction capability. Feed consumption and body and organ weights were recorded and histologic and ultrastructural changes were evaluated. Significant effects on feed intake and body weight occurred only at 10 or 100 ppm of 3,3′,4,4′,5,5′-HBB. Therefore, two of six rats given 100 ppm of 3,3′,4,4′,5,5′-HBB were continued on the diet until death occurred at 20 days. Liver weights were increased by each of the three chemicals at 10 and 100 ppm. Hepatocytes were diffusely enlarged and contained lipid vacuoles. The degree of vacuolation was dose related, most prominent in the centrolobular to midzonal area, and most severe in rats given 3,3′,4,4′,5,5′-HBB. Thymic and splenic weights were decreased at 10 and 100 ppm of 3,3′,4,4′,5,5′-HBB and lymphocytic depletion was severe in the thymus. Ultrastructural hepatic lesions were seen with all three chemicals. For 2,2′,4,4′,5,5′-HBB and FM BP-6 at 10 and 100 ppm the changes consisted mainly of increased smooth endoplasmic reticulum and lipid vacuolation. Additional changes seen with 3,3′,4,4′,5,5′-HBB included disorganization of rough endoplasmic reticulum, myelin body formation, and bile ductule hyperplasia. Results indicated that 3,3′,4,4′,5,5′-HBB causes more severe pathologic effects than either FM BP-6 or 2,2′,4,4′,5,5′-HBB.

Polybrominated biphenyls as promoters in experimental hepatocarcinogenesis in rats.

Female Sprague Dawley rats were fed polybrominated biphenyls (PBB) for six months after a 70% partial hepatectomy and diethylnitrosamine administration (10 mg/kg body weight) to determine if PBB could serve as a tumor promoter in a two stage hepatocarcinogenesis test system. Firemaster BP-6, a commercial mixture of PBB, and its major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB) were used in this study. Tumor promoting ability was assessed by measuring enzyme altered foci exhibiting gamma glutamyl transpeptidase activity. Dietary concentrations of 10 and 100 p.p.m. of the mixture of PBB and of HBB were found to be promoters of hepatocarcinogenesis. The mixture of PBB had a greater tumor promoting ability than HBB.

Toxic effects of dietary polybrominated biphenyls on mink

Serial levels of fireMaster FF-1, a commercial mixture of polybrominated biphenyls (PBB), and tissues from chickens and a cow that had previously consumed PBB were fed to mink to ascertain the chronic effects of the commercial and "metabolized" form of this compound on mink. Diets that contained 6.25 ppm (or more) PBB were lethal to adult mink within 10 months. One to 2.5 ppm dietary PBB fed for 9 months had an adverse effect on litter size, kit weight at birth, and kit survival. The data suggest that the PBB derived from contaminated beef and poultry was more toxic than the original PBB. The clinical signs of PBB poisoning in mink were food rejection, weight loss, and unthrifty appearance, and fatty infiltration of the liver. Based on these findings, mink must be considered highly susceptible to PBB toxicity. PBB residue levels 60 times the amount in the diet were found in the adipose tissue of the PBB-treated animals.

Toxicity of Polybrominated Biphenyl and Its Effects on Reproduction of White Leghorn Hens

White Leghorn hens were fed 0, 20, 64, 200, 640, and 2000 ppm of a commercial mixture of polybrominated biphenyls (BP-6). The lower levels of BP-6 (20 and 64 ppm) did not change feed intake. After 8 weeks, egg production was 59%, 51% and 39%, and hatchability was 85%, 65% and 11% for the hens fed 0, 20 and 64 ppm BP-6, respectively. During the second week of feeding 200 ppm BP-6, feed consumption was reduced to 85 g/hen/day, a 23% reduction in intake, and all hens fed 200 ppm stopped egg production within 3 weeks. Hens fed 640 and 2000 ppm refused feed immediately, and at the end of 1 week, feed consumption was 30% that of the control. During the second week of treatment, hatchability was 43%, 21%, and 43% for hens fed 200, 640, and 2000 ppm BP-6, respectively. Dead embryos had subcutaneous edema in the neck and rump areas. The day-old chicks that survived had a higher mortality and lower body weight gains during the 3-week growth test than the control progeny had. The concentration of BP-6 in the egg reached a plateau by the 4th week of feeding; the maximum concentration in the egg was 1.5 times the dietary level. When the BP-6 was replaced with uncontaminated feed, feed consumption returned to normal; and within 8 weeks, egg production of the hens fed 200, 640, and 2000 ppm BP-6 was similar to that of the control. After withdrawal of the BP-6, the concentration of BP-6 in the eggs of hens fed 20 and 64 ppm BP-6 decreased rapidly during the first 2 weeks. After the first 2 weeks, the concentration declined much less rapidly, and detectable amounts were still present 33 weeks after withdrawal of BP-6 from the diet.