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  • 1
    Online Resource
    Online Resource
    SAGE Publications ; 1994
    In:  Veterinary Pathology Vol. 31, No. 2 ( 1994-03), p. 173-182
    In: Veterinary Pathology, SAGE Publications, Vol. 31, No. 2 ( 1994-03), p. 173-182
    Abstract: The gross, microscopic, and ultrastructural features of lipomatous lesions in the liver of B6C3F1 mice are described. The cases were selected from a database of 45,406 male and 45,674 female mice used as treated, control, or vehicle-control animals in the National Cancer Institute's Bioassays or the National Toxicology Program's 2-year carcinogenicity studies. Thirteen hepatic lesions identified from cases within the database were re-evaluated microscopically and selected for further study. These lesions were present in ten males and three females that were between 85 and 113 weeks of age at the time of death. Grossly, the liver lesions were described as white to yellow or red to brown nodules/masses or foci that ranged from 2.0 to 25 mm in diameter. The lesions commonly involved the median and left lateral hepatic lobes. Microscopically, many of the lesions closely resembled lipomas described in the liver of human beings, and they consisted of nonencapsulated mature adipose-like tissue with irregular margins. The majority of the cells that comprised the lipomatous lesions were signet-ring shaped. These cells were positive for lipid as evidenced with oil red-O. The lipid droplets were also present within the hepatocytes that comprised the hepatic plates trapped within or surrounding many of the lipomatous lesions. At the margins of many of the lesions there were spindle-shaped cells that contained small intracytoplasmic lipid vacuoles. These cells were often within a stromal matrix that had focal areas of collagen and mucopolysaccharides, as evidenced by weak staining with Masson's trichrome and periodic acid-Schiff's stains, respectively. There was also disruption of the reticulum fibers in many of the lesions, as noted with a Gomori's reticulum stain. Ultrastructurally, cytoplasmic organelles, such as rough endoplasmic reticulum, free ribosomes and small lipid vacuoles, were present in the spindle-shaped cells, whereas signet-ring-shaped cells had few discernible organelles due to peripheral compression of the cytoplasm by single large vacuoles occupying the cytoplasmic space. The spindle-shaped cells were free of lysosomes. Thin collagen fibers were seen in contact with some of the spindle-shaped cells and were located between these cells and adjacent hepatocytes, or endothelial cells lining sinusoidal capillaries. A distinct basal lamina was not associated with spindle- or signet-ring-shaped cells. Similar lipomatous lesions were not found in other visceral organs. The exact cellular origin of the hepatic lesions described here is not known.
    Type of Medium: Online Resource
    ISSN: 0300-9858 , 1544-2217
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1994
    detail.hit.zdb_id: 2106608-5
    SSG: 22
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  • 2
    Online Resource
    Online Resource
    SAGE Publications ; 2010
    In:  Toxicologic Pathology Vol. 38, No. 7 ( 2010-12), p. 1009-1010
    In: Toxicologic Pathology, SAGE Publications, Vol. 38, No. 7 ( 2010-12), p. 1009-1010
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2010
    detail.hit.zdb_id: 2056753-4
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  • 3
    Online Resource
    Online Resource
    SAGE Publications ; 1989
    In:  Toxicologic Pathology Vol. 17, No. 4_part_1 ( 1989-04), p. 675-684
    In: Toxicologic Pathology, SAGE Publications, Vol. 17, No. 4_part_1 ( 1989-04), p. 675-684
    Abstract: Altered hepatocellular foci (AHF) can be reliably identified in hematoxylin and eosin (H & E)-stained sections of liver from interim and final sacrifice intervals in 2-yr carcinogenicity studies in rats. While most AHF can be categorized on the basis of a defined set of descriptive terms, viz., basophilic, eosinophilic, clear, vacuolated, and mixed foci, exposure to hepatocarcinogenic agents may induce unique types of AHF which should be distinguished from those that occur more commonly. It is proposed that unique treatment-associated AHF be classified as atypical AHF and that they be completely described in the pathology narrative accompanying the study. Since profound changes in the number and size of AHF have been documented in Fischer 344 rats with mononuclear cell leukemia, it is recommended that liver focus data from leukemic animals be censored in assessing potential effects of treatment on AHF. At the present time, there are insufficient data to allow routine use of AHF in regulatory decision-making in the absence of a liver tumor response. However, such data may form part of weight-of-evidence considerations used by regulatory bodies when accompanied by a concomitant liver tumor response.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1989
    detail.hit.zdb_id: 2056753-4
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  • 4
    Online Resource
    Online Resource
    SAGE Publications ; 1989
    In:  Toxicologic Pathology Vol. 17, No. 4_part_1 ( 1989-04), p. 579-593
    In: Toxicologic Pathology, SAGE Publications, Vol. 17, No. 4_part_1 ( 1989-04), p. 579-593
    Abstract: Quantitative evaluation of altered hepatocellular foci (AHF), followed by stereological analysis was performed on standard hematoxylin and eosin-stained liver sections from control Fischer 344 (F344) rats of both sexes from seven 2-yr carcinogenicity studies conducted by the National Toxicology Program (NTP). Liver samples were collected at 6, 9, 12, 15, 18, and/or 24 months on study. Although AHF had a broad spectrum of morphological features, they could be classified into the following 5 types using previously published criteria: basophilic, eosinophilic, clear, vacuolated, and mixed cell foci. Approximately 50% of the animals had foci at 6 months, and the incidence reached nearly 100% at 15 months in both sexes. The number, size and volume fraction of AHF increased with age in both sexes; these changes were most evident for basophilic and clear cell foci. The number of basophilic foci was significantly greater in females than in males while clear cell foci were more numerous in males. This sex difference was observed at each time point. Mean number of all types of AHF in males and females at 24 months was 547 and 460 per cubic centimeter of liver, respectively. Despite the high incidence of AHF in control rats, the incidence of hepatocellular neoplasms is low. The implication is that most foci do not progress to neoplasia in control F344 rats used in 2-yr studies.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1989
    detail.hit.zdb_id: 2056753-4
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  • 5
    Online Resource
    Online Resource
    Japanese Society of Toxicologic Pathology ; 1990
    In:  Journal of Toxicologic Pathology Vol. 3, No. 2 ( 1990), p. 161-188
    In: Journal of Toxicologic Pathology, Japanese Society of Toxicologic Pathology, Vol. 3, No. 2 ( 1990), p. 161-188
    Type of Medium: Online Resource
    ISSN: 0914-9198 , 1881-915X
    Language: English
    Publisher: Japanese Society of Toxicologic Pathology
    Publication Date: 1990
    detail.hit.zdb_id: 2128461-1
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  • 6
    Online Resource
    Online Resource
    SAGE Publications ; 1994
    In:  Toxicologic Pathology Vol. 22, No. 2 ( 1994-03), p. 105-111
    In: Toxicologic Pathology, SAGE Publications, Vol. 22, No. 2 ( 1994-03), p. 105-111
    Abstract: Toxicity/carcinogenicity studies in rodents have played a pivotal role in identifying chemicals that are potentially hazardous to humans. In fact, nearly all of the known human carcinogens are also carcinogenic in 1 or more rodent species. During the past 20 yr the quality and consistency of rodent studies has improved considerably, and much has been learned about mechanisms whereby chemicals initiate or promote the carcinogenic process in rats and mice. The process of identifying chemicals that cause toxicity or carcinogenicity in rodents is quite well established, but the procedures for extrapolating this data for risk management decisions in the protection of human health have lagged far behind. While many would accept the assumptions that genotoxic chemicals that cause cancer in animals pose a cancer risk to humans and that genotoxic chemicals causing cancer at high doses pose a risk at lower doses, there is much less certainty with respect to nongenotoxic chemicals. The confusion about risk extrapolation for nongenotoxic chemicals has often lead to criticism of the hazard identification process for chemicals in general. There is increasing awareness of the complexity of the carcinogenic process that has made species extrapolation and dose extrapolation from rodent studies to humans more complex. Although newer molecular biological techniques and cell kinetic measurements offer exciting possibilities for better risk assessment, it is the combination of well- designed rodent studies with appropriate mechanistic studies that offers the best hope for regulatory decisions based on sound scientific principles.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1994
    detail.hit.zdb_id: 2056753-4
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  • 7
    Online Resource
    Online Resource
    SAGE Publications ; 1986
    In:  Toxicologic Pathology Vol. 14, No. 2 ( 1986-02), p. 263-273
    In: Toxicologic Pathology, SAGE Publications, Vol. 14, No. 2 ( 1986-02), p. 263-273
    Abstract: Diagnostic criteria for hepatoproliferative lesions of Fischer 344 rats are presented to permit more complete categorization of the spectrum of lesions observed in two-year chemical carcinogenicity studies. A nomenclature recently adopted by the National Toxicology Program differs from previous classification schemes in that hepatocellular hyperplasia and hepatocellular adenoma are to be used for lesions which were previously combined under the diagnosis of neoplastic nodule. The term hyperplasia is reserved for proliferative lesions that are perceived to be secondary, nonneoplastic responses to degenerative changes in the liver. Foci of cellular alteration, hepatocellular adenoma, and hepatocellular carcinoma are believed to represent a spectrum of changes that comprise the natural history of neoplasia. This change in nomenclature was made subsequent to a peer review of representative hepatoproliferative lesions from two-year carcinogenicity studies. The revised nomenclature is consistent with traditional pathologic diagnoses for proliferative lesions in other epithelial tissues and should facilitate the interpretation of conventional toxicity and carcinogenicity studies in rats. Morphologic features of other selected rat liver lesions are also presented.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1986
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  • 8
    Online Resource
    Online Resource
    SAGE Publications ; 1989
    In:  Toxicologic Pathology Vol. 17, No. 4_part_1 ( 1989-04), p. 690-708
    In: Toxicologic Pathology, SAGE Publications, Vol. 17, No. 4_part_1 ( 1989-04), p. 690-708
    Abstract: Retrospective characterization of morphological and stereological features of altered hepatocellular foci (AHF) in hematoxylin & eosin (H & E)-stained sections was performed on 6 conventional 2−yr carcinogenicity studies conducted in Fischer 344 (F344) rats by the National Toxicology Program (NTP). In 3 of these studies where there was clear evidence of hepatocarcinogenicity [1−amino−2,4−dibromoanthraquinone (ADBAQ), C.I. Acid Red 114, methyl carbamate], there was greater morphological variability in AHF than in the studies of chemicals that were not hepatocarcinogenic [4−hydroxyacetanilide, epinephrine, dimethoxane] . In addition to having the expected types of AHF, rats treated with ADBAQ, C.I. Acid Red 114, and methyl carbamate had atypical basophilic AHF. In addition, atypical eosinophilic AHF were present in rats treated with ADBAQ. Both types of atypical AHF showed a morphological spectrum and sequential changes suggesting they could develop into hepatocellular neoplasms. For the 3 liver tumor positive studies, there were dose-and time-dependent increases in stereological parameters for the atypical as well as commonly occurring clear, vacuolated, and mixed cell AHF. Consistent stereological changes were not found for commonly occurring basophilic and eosinophilic AHF. Aside from some decreases in stereological measurements in some rats treated with 4−hydroxyacetanilide and epinephrine, there were no significant quantitative changes in AHF in the three liver tumor negative studies. These results show that hepatocarcinogens may induce unique types of AHF in conventional 2−yr carcinogenicity/toxicity studies in rats and may cause quantitative increases in commonly occurring clear, vacuolated, and mixed cell AHF. Such qualitative and quantitative changes are potentially useful predictors of hepatic neoplasia.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 1989
    detail.hit.zdb_id: 2056753-4
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  • 9
    In: Toxicologic Pathology, SAGE Publications, Vol. 47, No. 1 ( 2019-01), p. 11-17
    Abstract: A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice ( p 〈 .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
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