المؤلفون: Warheit, David B., Reed, Kenneth L., DeLorme, Michael P.

المصدر: Toxicologic Pathology; 2/1/2013, Vol. 41 Issue 2, p387-394, 8p

مصطلحات موضوعية: TOXICOLOGY of poisonous gases, PHYSIOLOGICAL effects of nanoparticles, CARBON nanofibers, DRUG side effects, BRONCHOALVEOLAR lavage, CELL proliferation, ALKALINE phosphatase, LACTATE dehydrogenase, LABORATORY rats

الشركة/الكيان: ORGANISATION for Economic Co-operation & Development

مستخلص: The goal of this article is to evaluate a recently published subchronic inhalation study with carbon nanofibers in rats and discuss the importance of a weight-of-evidence (WOE) framework for determining no adverse effect levels (NOAELs). In this Organization for Economic Cooperation and Development (OECD) 413 guideline inhalation study with VGCF™-H carbon nanofibers (CNFs), rats were exposed to 0, 0.54, 2.5 or 25 mg/m3 CNF for 13 weeks. The standard toxicology experimental design was supplemented with bronchoalveolar lavage (BAL) and respiratory cell proliferation (CP) endpoints. BAL fluid (BALF) recovery of inflammatory cells and mediators (i.e., BALF– lactate dehydrogenase [LDH], microprotein [MTP], and alkaline phosphatase [ALKP] levels) were increased only at 25 mg/m3, 1 day after exposure. No differences versus control values in were measured at 0.54 or 2.5 mg/m3 exposure concentrations for any BAL fluid endpoints. Approximately 90% (2.5 and 25 mg/m3) of the BAL-recovered macrophages contained CNF. CP indices at 25 mg/m3 were increased in the airways, lung parenchyma, and subpleural regions, but no increases in CP versus controls were measured at 0.54 or 2.5 mg/m3. Based upon histopathology criteria, the NOAEL was set at  0.54 mg/m3, because at 2.5 mg/m3, “minimal cellular inflammation” of the airways/lung parenchyma was noted by the study pathologist; while the 25 mg/m3 exposure concentration produced slight inflammation and occasional interstitial thickening. In contrast, none of the more sensitive pulmonary biomarkers such as BAL fluid inflammation/cytotoxicity biomarkers or CP turnover results at 2.5 mg/m3 were different from air-exposed controls. Given the absence of convergence of the histopathological observations versus more quantitative measures at 2.5 mg/m3, it is recommended that more comprehensive guidance measures be implemented for setting adverse effect levels in (nano)particulate, subchronic inhalation studies including a WOE approach for establishing no adverse effect levels; and a suggestion that some findings should be viewed as normal physiological adaptations (e.g., normal macrophage phagocytic responses—minimal inflammation) to long-term particulate inhalation exposures. [ABSTRACT FROM PUBLISHER]

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المؤلفون: David B. Warheit, Kenneth L. Reed, Michael P. DeLorme

المصدر: Toxicologic Pathology. 41:387-394

مصطلحات موضوعية: Male, Pathology, medicine.medical_specialty, Pulmonary toxicity, Nanofibers, Pharmacology, Toxicology, Pathology and Forensic Medicine, Rats, Sprague-Dawley, chemistry.chemical_compound, Lactate dehydrogenase, Toxicity Tests, Parenchyma, medicine, Animals, Respiratory system, Lung, Molecular Biology, Cell Proliferation, Aerosols, Inhalation Exposure, medicine.diagnostic_test, Inhalation, Cell Biology, Carbon, Rats, Bronchoalveolar lavage, chemistry, Toxicity, Alkaline phosphatase, Female, Bronchoalveolar Lavage Fluid

الوصف: The goal of this article is to evaluate a recently published subchronic inhalation study with carbon nanofibers in rats and discuss the importance of a weight-of-evidence (WOE) framework for determining no adverse effect levels (NOAELs). In this Organization for Economic Cooperation and Development (OECD) 413 guideline inhalation study with VGCF™-H carbon nanofibers (CNFs), rats were exposed to 0, 0.54, 2.5 or 25 mg/m3 CNF for 13 weeks. The standard toxicology experimental design was supplemented with bronchoalveolar lavage (BAL) and respiratory cell proliferation (CP) endpoints. BAL fluid (BALF) recovery of inflammatory cells and mediators (i.e., BALF– lactate dehydrogenase [LDH], microprotein [MTP], and alkaline phosphatase [ALKP] levels) were increased only at 25 mg/m3, 1 day after exposure. No differences versus control values in were measured at 0.54 or 2.5 mg/m3 exposure concentrations for any BAL fluid endpoints. Approximately 90% (2.5 and 25 mg/m3) of the BAL-recovered macrophages contained CNF. CP indices at 25 mg/m3 were increased in the airways, lung parenchyma, and subpleural regions, but no increases in CP versus controls were measured at 0.54 or 2.5 mg/m3. Based upon histopathology criteria, the NOAEL was set at 0.54 mg/m3, because at 2.5 mg/m3, “minimal cellular inflammation” of the airways/lung parenchyma was noted by the study pathologist; while the 25 mg/m3 exposure concentration produced slight inflammation and occasional interstitial thickening. In contrast, none of the more sensitive pulmonary biomarkers such as BAL fluid inflammation/cytotoxicity biomarkers or CP turnover results at 2.5 mg/m3 were different from air-exposed controls. Given the absence of convergence of the histopathological observations versus more quantitative measures at 2.5 mg/m3, it is recommended that more comprehensive guidance measures be implemented for setting adverse effect levels in (nano)particulate, subchronic inhalation studies including a WOE approach for establishing no adverse effect levels; and a suggestion that some findings should be viewed as normal physiological adaptations (e.g., normal macrophage phagocytic responses—minimal inflammation) to long-term particulate inhalation exposures.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8a16d29fa104596c8898f711c7cecea7Test
https://doi.org/10.1177/0192623312467401Test

المؤلفون: Nobuyuki Ito, Akihiro Hagiwara, Masao Hirose, Emiko Asakawa, Yasushi Kurata, Masashi Sano

المصدر: Toxicologic Pathology. 20:197-204

مصطلحات موضوعية: Male, medicine.medical_specialty, Brush border, 040301 veterinary sciences, Urinary system, Drinking, Urination, Urine, Toxicology, 030226 pharmacology & pharmacy, Acetylglucosamine, Pathology and Forensic Medicine, 0403 veterinary science, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Phagocytosis, Oral administration, Lactate dehydrogenase, Internal medicine, medicine, Animals, Molecular Biology, Kidney, L-Lactate Dehydrogenase, Microvilli, DNA, Organ Size, 04 agricultural and veterinary sciences, Cell Biology, Rats, Inbred F344, Rats, Harmine, Kidney Tubules, Endocrinology, medicine.anatomical_structure, Bromodeoxyuridine, chemistry, Toxicity, Alkaline phosphatase, Kidney Diseases, Carbolines

الوصف: The renal toxicity of harman and norharman, administered for 2 or 4 weeks at dietary levels of 1,000, 500, or 0 parts per million (ppm), was investigated in 6-week-old male F344/DuCrj rats. Although rats fed 1,000 ppm harman or norharman, but not the 500 ppm level, demonstrated marked body weight retardation from 1 week to termination, no mortalities occurred. Marked elevation of water consumption was evident in rats given harman or norharman at 1,000 ppm, but not at 500 ppm, together with large increases in urine of low specific gravity. Urinary lysosomal enzymes ( N-acetyl-βT-D-glucosaminidase, NAG, and lactate dehydrogenase, LDH) and sugar levels were increased, and the brush border enzymes (γ-glutamyl transpeptidase, GGT, and alkaline phosphatase, ALP) decreased. Furthermore, serum biochemistry revealed clear elevation of parameters indicating renal toxicity in these rats. Histopathologically, rats fed 1,000 ppm harman or norharman, but not 500 ppm, demonstrated focal toxic renal degenerative/necrotic and regenerative lesions in proximal, distal, and collecting tubules. These changes were associated with a clearly increased labeling index (LI) of the nuclei of renal tubular epithelial cells on immunohistochemical staining for 5-bromo-2′-deoxyuridine (BrdU). Chemical specific crystal formation within tubular lumina was evident in rats fed 1,000 ppm, but not 500 ppm, this being considered the cause of the renal tubular lesions. It was concluded that harman and norharman exert renal toxicity at the dietary level of 1,000 ppm, but not 500 ppm, in male F344 rats.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2a36fee3b9f5a86c5db261f54f2ec24Test
https://doi.org/10.1177/019262339202000206Test

المؤلفون: Shingo Arakawa, Kazunori Fujimoto, Yosuke Ando, Sunao Manabe, Kazuyoshi Kumagai, Kazumi Ito, Takashi Yamoto, Sen-ichi Oda

المصدر: Toxicologic pathology. 37(2)

مصطلحات موضوعية: medicine.medical_specialty, Heterozygote, Time Factors, Cell Survival, SOD2, Mitochondria, Liver, Toxicology, Sensitivity and Specificity, Pathology and Forensic Medicine, Gene Knockout Techniques, Mice, Necrosis, Troglitazone, Adenosine Triphosphate, Internal medicine, medicine, Animals, Aspartate Aminotransferases, Chromans, skin and connective tissue diseases, Molecular Biology, Cells, Cultured, Acetaminophen, Liver injury, Mice, Knockout, Dose-Response Relationship, Drug, L-Lactate Dehydrogenase, business.industry, Superoxide Dismutase, Centrilobular necrosis, Alanine Transaminase, Cell Biology, medicine.disease, Alkaline Phosphatase, Mitochondrial toxicity, Dose–response relationship, Endocrinology, Liver, Toxicity, Models, Animal, cardiovascular system, Hepatocytes, Thiazolidinediones, business, medicine.drug

الوصف: Recently, it was reported that the intraperitoneal administration of 30 mg/kg/day troglitazone to heterozygous superoxide dismutase 2 gene knockout (Sod2+/−) mice for twenty-eight days caused liver injury, manifested by increased serum ALT activity and hepatic necrosis. Therefore, we evaluated the reproducibility of troglitazone-induced liver injury in Sod2+/− mice, as well as their validity as an animal model with higher sensitivity to mitochondrial toxicity by single-dose treatment with acetaminophen in Sod2+/− mice. Although we conducted a repeated dose toxicity study in Sod2+/− mice treated orally with 300 mg/kg/day troglitazone for twenty-eight days, no hepatocellular necrosis was observed in our study. On the other hand, six hours and twenty-four hours after an administration of 300 mg/kg acetaminophen, plasma ALT activity was significantly increased in Sod2+/− mice, compared to wild-type mice. In particular, six hours after administration, hepatic centrilobular necrosis was observed only in Sod2+/− mice. These results suggest that Sod2+/− mice are valuable as an animal model with higher sensitivity to mitochondrial toxicity. On the other hand, it was suggested that the mitochondrial damage alone might not be the major cause of the troglitazone-induced idiosyncratic liver injury observed in humans.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e89e166f2644155b348ab9e0515f72aeTest
https://pubmed.ncbi.nlm.nih.gov/19332662Test

المؤلفون: V.S. Turusov, Galina Chemeris, Young Soo Ahn, Peter Bannasch

المصدر: Toxicologic pathology. 22(4)

مصطلحات موضوعية: Male, medicine.medical_specialty, Pathology, 040301 veterinary sciences, Biology, Toxicology, 030226 pharmacology & pharmacy, Pathology and Forensic Medicine, 0403 veterinary science, 03 medical and health sciences, chemistry.chemical_compound, Glycogen phosphorylase, Mice, 0302 clinical medicine, Lactate dehydrogenase, Internal medicine, medicine, Animals, Glycolysis, Glycogen synthase, Molecular Biology, Dimethylhydrazines, Hexokinase, Glycogen, Histocytochemistry, 04 agricultural and veterinary sciences, Cell Biology, Kidney Neoplasms, 1,2-Dimethylhydrazine, Endocrinology, chemistry, biology.protein, Carcinogens, Mice, Inbred CBA, Alkaline phosphatase, Precancerous Conditions, Pyruvate kinase

الوصف: Mouse renal cell tumors (RCTs) were induced in male CBA mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH)/kg body weight once a week. After a lag period of 2 yr kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glycogen content, basophilia, and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and γ-glutamyltranspeptidase (GGT). RCTs displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with the normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK, LDH) and the pentose phosphate pathway (G6PDH), while negative G6Pase and low SDH activity were observed in these cells. The majority of RCTs showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCTs. Markedly enlarged cells with atypical nuclei were detected in some advanced RCTs. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in these enlarged cells than in other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in RCTs in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early during carcinogenesis, but additional studies on early stages of renal carcinogenesis are needed to substantiate this assumption.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::36f228cbf5ebf1e3365d659718a0837bTest
https://pubmed.ncbi.nlm.nih.gov/7817130Test

المؤلفون: Benjamin F. Trump, Shreekant Chopra, James S. Kaufman, Thomas W. Jones, Walter Flamenbaum

المصدر: Toxicologic Pathology. 13:296-305

مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, ATPase, Acid Phosphatase, Glycerolphosphate Dehydrogenase, Dehydrogenase, Toxicology, Pathology and Forensic Medicine, 03 medical and health sciences, Internal medicine, medicine, Animals, Gamma-glutamyltransferase, Molecular Biology, chemistry.chemical_classification, L-Lactate Dehydrogenase, 030102 biochemistry & molecular biology, biology, Histocytochemistry, Succinate dehydrogenase, Acid phosphatase, Acute kidney injury, Rats, Inbred Strains, gamma-Glutamyltransferase, Cell Biology, Acute Kidney Injury, Alkaline Phosphatase, medicine.disease, Rats, Succinate Dehydrogenase, Kidney Tubules, 030104 developmental biology, Enzyme, Endocrinology, chemistry, Glucose-6-Phosphatase, biology.protein, Alkaline phosphatase, Cisplatin, Sodium-Potassium-Exchanging ATPase

الوصف: Enzyme histochemical techniques were utilized to examine the progression and extent of proximal tubular injury during the development of cis-diamminedichloroplatinum (II) (CDDP)-induced acute renal failure. Acute renal failure was induced in male rats by the intraperitoneal administration of 10 mg CDDP/kg body weight. At 6, 24, 48, 72, and 96 hr following treatment, renal function was assessed and tissue was collected for renal morphologic and enzyme histochemical studies. The enzymes examined were γ-glutamyl transpeptidase, alkaline phosphatase, sodium-potassium ATPase (nitrophenyl phosphatase), acid phosphatase, glucose-6-phosphatase, succinic dehydrogenase, α-glycerophosphate dehydrogenase, and lactic dehydrogenase. By 24 hr, the activity of acid phosphatase was reduced throughout the proximal tubule, with the greatest decrease occurring in the P3 segment of the proximal tubule located in the outer stripe of the outer medulla. Changes in the histochemical staining of the remaining enzymes were not consistently observed until 48 or, in some cases, 72 hr. These alterations involved all portions of the proximal tubule with the most severe changes involving P3. The results of the enzyme histochemical studies along with the morphologic findings indicating that the initiation of CDDP-induced acute renal failure, first apparent at 48 hr in this model, is associated with cell injury throughout the proximal tubule. The majority of the histochemical changes did not become apparent until late in the course of tubular injury. This suggests that most of the changes in enzyme activity represent nonspecific effects of CDDP-induced tubular injury, as opposed to direct enzyme inhibition by the drug.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6120362fefc631da53801d88209203e1Test
https://doi.org/10.1177/019262338501300406Test