Promoting effect of polychlorinated biphenyls on development of enzyme-altered islands in livers of weanling and adult rats

Oesterle, Doris; Deml, E.

doi:10.1007/bf00406924

Cited by 42 publications

(15 citation statements)

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“…in juvenile rats as test animals, has been developed in one of the participating laboratories and employed in several studies prior to the present prevalidation study (16,41,42). During the initial phases of the RLFB prevalidation project, Standard Operating Procedures (SOPs) were developed, which describe in detail all essential aspects of the animal study, including the morphometric evaluation of FAH and the statistical analysis of the data.…”

Section: Discussionmentioning

confidence: 99%

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

et al. 2003

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A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione-S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.

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Section: Discussionmentioning

confidence: 99%

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

et al. 2003

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“…Vacuolated or clear cell foci have been reported in aging F344 rats but are difficult to detect (22). Polychlorinated biphenyls were shown to be promoters of liver foci and tumors in short term in vivo assays (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The findings in this study suggest that they may also be initiators.…”

Section: Discussionmentioning

confidence: 99%

“…Polychlorinated biphenyls (PCBs) have been shown to induce liver tumors in rats (1)(2)(3)(4)(5)) and mice (6)(7)(8) and to promote development of liver preneoplastic foci and tumors initiated by other carcinogens in liver (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In the early 1970s, little was known of the carcinogenic potential of PCBs.…”

Section: Introductionmentioning

confidence: 99%

Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254.

Ward¹

1985

Environ Health Perspect

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Aroclor 1254 was fed to groups of 24 male and 24 female F344 rats, from 7 weeks of age, at dietary concentrations of 25, 50 and 100 ppm for up to 105 weeks. There was a dose-related depression of body weight gain for both sexes and decrease in survival for male rats. Histologically, an increased incidence of gastric intestinal metaplasia and adenocarcinoma was found in both sexes. Hepatocellular adenomas, carcinomas, and eosinophilic and vacuolated hepatocellular foci were usually found in dosed rats only. The number of these foci per unit area of liver was significantly increased in dosed rats, although eosinophilic foci were only found in rats exposed to Aroclor 1254. Basophilic hepatocellular foci were found in similar numbers per square centimeter of liver in controls and treated rats. This finding suggested that eosinophilic hepatocellular foci and tumors arose de novo rather than from the naturally occurring basophilic foci. The appearance of unique, potentially preneoplastic lesions and tumors in the liver and stomach in dosed rats which do not usually occur spontaneously in control rats would support the hypothesis that Aroclor 1254 induced or initiated these unique lesions de novo rather than promoted the growth of any naturally occurring lesions. Nonneoplastic hepatic lesions included degenerative hepatocellular changes and aggregates of macrophages with crystalline cytoplasmic structures and pigment granules.

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“…By using such procedures, Deml and Oesterle (18) found that Clophen A 50, a commercial mixture of PCBs, had greater promoting effects in livers from female rats when compared to the effects in males. They also reported that weanling rats were much more susceptible to the promoting effects of PCBs than adult rats (19).…”

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Effects of PCBs and Related Compounds on Hepatocarcinogenesis in Rats and Mice

Sleight¹

1985

Environmental Health Perspectives

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Commercial mixtures of polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) can cause hepatocellular carcinoma in rats and mice. Present evidence indicates that these chemicals act as promoters and not initiators of hepatocarcinogenesis. Our results show that Firemaster BP-6 (FM) and its nontoxic major congener, 2,2',4,4',5,5'-hexabromobiphenyl (HBB), act as promoters in the two-stage model for hepatocarcinogenesis devised by Pitot and associates. A toxic congener, 3,3',4,4',5,5'-HBB, also was assessed for tumor-promoting activity. This congener, though not in FM, is similar to TCDD, in that both cause 3-methylcholanthrene (MC)-type induction of hepatic microsomal enzymes and produce similar toxic responses. FM contains several congeners which are mixed-type inducers in that they induce MC-type and phenobarbital (PB)-type enzymes. The toxicity of FM is most likely associated with its congeners which are mixed-type inducers and not to relatively nontoxic congeners such as 2,2',4,4',5,5'-HBB which are strictly PB-type inducers. Congener 3,3',4,4',5,5'-HBB acted as a tumor promoter only at a dose that was hepatotoxic. A synergistic effect on tumor promoting ability was produced by combining a nontoxic and nonpromoting dose of 3,3',4,4',5,5'-HBB with a promoting dose of 2,2',4,4',5,5'-HBB. Our results suggest that synergism between toxic and nontoxic congeners in FM may explain why mixtures such as FM have greater promoting ability than individual congeners. Our results also indicate that with PBB, toxicity and carcinogenicity are not necessarily related.One of the major concerns of people exposed to environmental chemicals such as polychlorinated biphenyls (PCBs) is whether or not these chemicals are carcinogenic. Although epidemiologic studies have not conclusively shown a greater cancer risk for people as a result of PCB exposure, there is conclusive evidence that PCBs can cause hepatic cancer in rodents. Prolonged dietary administration of PCB mixtures has induced hepatic tumors in rats (1-4) and mice (5-7). Hepatocellular carcinomas were described in each species and, in addition, what are classified as neoplastic nodules and foci of cellular alteration were described (8).Evidence to date strongly indicates that the mixtures of PCBs act as promoters of hepatic carcinogenesis. When PCBs were given to rats after an initiator such as diethylnitrosamine there was convincing evidence that they had a tumor promoting effect in the liver (9,10).Thmor promotion was also evident when impurities such as dibenzofurans were removed from the PCB mixture (10). Earlier, Kimura et al. (11) reported a high incidence of hepatocellular carcinomas in the livers of rats fed a diet containing a tumor initiator, 3'-methyl-4-dimethylaminoazobenzene, for 2 months followed by dietary administration of Kanechlor 400, a commercial *Department of Pathology, Michigan State University, East Lansing, MI 48824. mixture of PCBs, for 6 months. Since administration of the initiator by itself or administration of Kanechlor before o...

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Promoting effect of polychlorinated biphenyls on development of enzyme-altered islands in livers of weanling and adult rats

Cited by 42 publications

References 14 publications

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report

Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254.

Effects of PCBs and Related Compounds on Hepatocarcinogenesis in Rats and Mice

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