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James E. Klaunig - One of the best experts on this subject based on the ideXlab platform.
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Kupffer cells participate in 2-Butoxyethanol-induced liver hemangiosarcomas.
Toxicology, 2010Co-Authors: Lisa M. Kamendulis, Stacy M Corthals, James E. KlaunigAbstract:2-Butoxyethanol increases hemangiosarcomas selectively in male mouse liver after chronic inhalation through mechanisms that have not fully been elucidated. Hemolysis, a primary toxic effect associated with 2-Butoxyethanol exposure in rodents, increased hemosiderin (iron) deposition in Kupffer cells in the liver. These findings, along with the induction of hepatic neoplastic lesions, led to our hypothesis that the induction hemangiosarcomas by 2-Butoxyethanol is due to the activation of Kupffer cells, subsequent to hemolysis, that results in the induction of DNA synthesis in target cells (endothelial cells); allowing for the selective proliferation of preneoplastic target cells and/or the promotion of new initiated cells. The present studies were conducted to determine whether Kupffer cells contributed to 2-Butoxyethanol-induced endothelial DNA synthesis in the liver, thereby determining whether a linkage exists between these events. Male B6C3F1 mice were treated with 450 and 900 mg/kg 2-Butoxyethanol (via daily gavage; 5x/week) for 7 days in the presence or absence of Kupffer cell depletion (via clodronate-encapsulated liposomes). 2-Butoxyethanol (450 and 900 mg/kg/day) increased the number of F4/80 stained cells (Kupffer cells) compared to controls (approximately 1.3- and approximately 1.6-fold over control, respectively). Clodronate liposome treatment reduced the number of Kupffer cells by >90%, as assessed by F4/80 immunohistochemistry. Increased hemolysis, measured by increases in relative spleen weights and decreased hematocrit was confirmed in 2-Butoxyethanol treated mice. The percentage of iron-stained endothelial cells increased by approximately 11-fold over control, and endothelial cell DNA synthesis increased approximately 1.7-fold over control in 2-Butoxyethanol exposed mice. Importantly, Kupffer cell depletion reduced 2-Butoxyethanol-induced iron staining and hepatic endothelial cell DNA synthesis. These studies provide evidence supporting the hypothesis that the Kupffer cell modulates 2-Butoxyethanol-induced endothelial cell DNA synthesis, and therefore may contribute to hemangiosarcoma induction by 2-Butoxyethanol.
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Mechanisms of 2-Butoxyethanol-induced hemangiosarcomas.
Toxicological Sciences, 2006Co-Authors: Stacy M Corthals, Lisa M. Kamendulis, James E. KlaunigAbstract:Chronic exposure to 2-Butoxyethanol increased liver hemangiosarcomas in male mice. The mechanism for the selective induction of hemangiosarcomas by 2-Butoxyethanol is unknown but has been suggested to occur through non–DNA-reactive mechanisms. The occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to RBC hemolysis and iron deposition and activation of macrophages (Kupffer cells) in the liver, events that exhibit a threshold in both animals and humans. 2-Butoxyethanol is metabolized to 2-butoxyacetaldehyde and 2butoxyacetic acid, and although the aldehyde metabolite is short lived, the potential exists for this metabolite to cause DNA damage. The present study examined whether 2-Butoxyethanol and its metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid, damaged mouse endothelial cell DNA using the comet assay. No increase in DNA damage was observed following 2-Butoxyethanol (1–10mM), 2-butoxyacetaldehyde (0.1–1.0mM), or 2-butoxyacetic acid (1–10mM) in endothelial cells after 2, 4, or 24 h of exposure. Additional studies examined the involvement of hemolysis and macrophage activation in 2-Butoxyethanol carcinogenesis. DNA damage was produced by hemolyzed RBCs (10 3 10 6 , 4 h), ferrous sulfate (0.1–1.0mM; 2–24 h), and hydrogen peroxide (50–100mM; 1–4 h) in endothelial cells. Hemolyzed RBCs also activated macrophages, as evidenced by increased tumor necrosis factor (TNF) a, while neither 2-Butoxyethanol nor butoxyacetic acid increased TNF-a from macrophages. The effect of activated macrophages on endothelial cell DNA damage and DNA synthesis was also studied. Coculture of endothelial cells with activated macrophages increased endothelial cell DNA damage after 4 or 24 h and increased endothelial cell DNA synthesis after 24 h. These data demonstrate that 2-Butoxyethanol and related metabolites do not directly cause DNA damage. Supportive evidence also demonstrated that damaged RBCs, iron, and/or products from macrophage activation (possibly reactive oxygen species) produce DNA damage in endothelial cells and that activated macrophages stimulate endothelial cell proliferation. These events coupled together provide the events necessary for the induction of hemangiosarco
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review of studies concerning the tumorigenicity of 2 Butoxyethanol in b6c3f1 mice and its relevance for human risk assessment
Journal of Toxicology and Environmental Health-part B-critical Reviews, 2004Co-Authors: Rodney J Boatman, Trevor Green, James E. Klaunig, Richard A Corley, Mark M UddenAbstract:The U.S. National Toxicology Program (NTP) has completed 2-yr inhalation exposures in rats and mice with 2-Butoxyethanol (BE). This review concerns the most significant findings from those studies and describes recent research into the mechanistic aspects of BE-mediated tumorigenesis in the mouse and the relevance of such effects to humans. Two tumor types were increased in B6C3F1 mice leading to the classification of “some evidence” of carcinogenicity: liver hemangiosarcomas in male mice and forestomach tumors in female mice (primarily benign papillomas). The results of research collected to date indicate that the tumorigenesis noted for BE was produced by indirect mechanisms. In particular, the occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition in this organ. Oral administration of BE in mice up to 600 mg/kg/d for up to 90 d produces a dose-related increase in iron (Perl’s staining) in Kupffer cells and hepatoc...
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Hepatic Effects of 2-Butoxyethanol in Rodents
Toxicological Sciences, 2002Co-Authors: Angela M. Siesky, Lisa M. Kamendulis, James E. KlaunigAbstract:Chronic inhalation of 2-Butoxyethanol resulted in an increase in liver hemangiosarcomas and hepatic carcinomas in male mouse liver. No increase in liver neoplasia was observed in similarly exposed male and female rats or female mice. We proposed that the production of liver neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of iron in the liver. This occurs selectively in the male mouse and leads either directly or indirectly to liver neoplasia. To address this proposal, male B6C3F1 mice and male F344 rats were treated with 2-Butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900 mg/kg/day (mice) and 0, 225, and 450 mg/kg/day (rats) respectively. Following treatment for 7, 14, 28, and 90 days, DNA synthesis, oxidative damage, hematocrit, and iron deposition were measured in the livers. An increase in hemolysis (measured by a decrease in hematocrit and increase in relative spleen weight) was observed in 2-Butoxyethanol-treated rats and mice in a dosedependent manner. An increase in the percentage of iron-stained Kupffer cells was observed following treatment with 450 and 900 mg/kg of 2-Butoxyethanol in mice and 225 and 450 mg/kg of 2-Butoxyethanol in rats. A biphasic increase in oxidative damage (8-hydroxydeoxyguanosine and malondialdehyde) was seen in mouse liver after 7 and 90 days of treatment with 2-Butoxyethanol, whereas no increases were observed in treated rat liver. Vitamin E levels were reduced by 2-Butoxyethanol treatment in both mice and rat liver; however, the basal level of vitamin E was approximately 2.5-fold higher in rat than in mouse liver. A similar biphasic induction of DNA synthesis was seen following 2-Butoxyethanol treatment in the mouse. In the mouse liver, increased DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in DNA synthesis was seen in 2-Butoxyethanol-treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between 2-Butoxyethanol treatment groups and untreated controls. These results suggest that DNA synthesis, possibly from oxidative stress or Kupffer cell activation, occurs selectively in the mouse liver, primarily in endothelial cells (a target of 2-Butoxyethanol neoplasia), following exposure to 2-Butoxyethanol.
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Mechanisms of 2-Butoxyethanol Carcinogenicity: Studies on Syrian Hamster Embryo (SHE) Cell Transformation
Toxicological Sciences, 2002Co-Authors: Joungjoa Park, Lisa M. Kamendulis, James E. KlaunigAbstract:Previous studies showed that 2-Butoxyethanol increased liver tumors in B6C3F1 mice following chronic exposure. While the mechanism of 2-Butoxyethanol-induced liver carcinogenicity has not been defined, 2-Butoxyethanol has been shown to induce hemolysis in rodents via 2-butoxyacetic acid, the major metabolite of 2-Butoxyethanol. This toxic effect, coupled with the observation that continued treatment with 2-Butoxyethanol results in hemosiderin deposition in the liver, has led to our hypothesis that liver carcinogenicity by 2-butoxyethnaol is mediated via oxidative stress (iron catalyzed) and Kupffer cell activation. The present study used Syrian Hamster Embryo (SHE) cell transformation, a surrogate in vitro model for carcinogenesis in vivo, to examine whether 2-Butoxyethanol, 2-butoxyacetic acid, or iron (ferrous sulfate) produced cell transformation. SHE cells were treated with either 2-Butoxyethanol (0.5‐20 mM), 2-butoxyacetic acid (0.5‐20 mM), or ferrous sulfate (0.5‐75 mg/ml) for 7 days. 2-Butoxyethanol and 2-butoxyacetic acid did not induce cellular transformation. In contrast, treatment with ferrous sulfate (2.5 and 5.0 mg/ml) increased morphological transformation. Cotreatment of ferrous sulfate with the antioxidants a-tocopherol (vitamin E) or (-)-epigallocatechin-3-gallate (EGCG) prevented ferrous sulfateinduced transformation, suggesting the involvement of oxidative stress in SHE cell transformation. The level of oxidative DNA damage (OH8dG) increased following ferrous sulfate treatment in SHE cells; additionally, using single cell gel electrophoresis (comet assay), ferrous sulfate treatment produced an increase in DNA damage. Both DNA lesions were decreased by cotreatment of ferrous sulfate with antioxidants. These data support our proposal that iron, produced indirectly through hemolysis, and not 2-Butoxyethanol or its metabolite 2-butoxyacetic acid, is responsible for the observed carcinogenicity of 2-Butoxyethanol.
Burhan I Ghanayem - One of the best experts on this subject based on the ideXlab platform.
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dental pulp infarction in female rats following inhalation exposure to 2 Butoxyethanol
Toxicologic Pathology, 2000Co-Authors: Philip H Long, Burhan I Ghanayem, Robert R Maronpot, Joseph H Roycroft, Abraham NyskaAbstract:Female Fischer 344 (F344)/N rats (10 per exposure group) were exposed to 2-Butoxyethanol (BE) vapors (0, 31, 62.5, 125, 250, or 500 ppm 6 h/d, 5 d/wk, for 13 weeks) to characterize its prechronic toxicity. Dental lesions consisting of bilateral multifocal dental pulp thrombosis, pulp infarction, and odontoblast infarction were noted in the maxillary incisors of 3 of 4 rats from the 500-ppm group that were sacrificed when moribund during the first week of exposure. In addition, 1 rat from the 500-ppm group that was sacrificed on day 32 had similar unilateral incisor lesions but with additional findings consistent with a unilateral maxillary incisor fracture. In contrast, rats sacrificed after 13 weeks of exposure lacked dental lesions. In conclusion, BE has the potential to cause pulp thrombosis and odontoblast infarction in female rats. The apparent variability in response to BE noted in moribund sacrificed vs terminally sacrificed rats was attributed to development of tolerance to BE-induced hemolysis and subsequent incisor regeneration.
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ocular thrombosis and retinal degeneration induced in female f344 rats by 2 Butoxyethanol
Human & Experimental Toxicology, 1999Co-Authors: Abraham Nyska, R R Maronpot, Burhan I GhanayemAbstract:2-Butoxyethanol, used extensively for domestic and industrial purposes, was tested in our experiments for its potential to cause damage to female rat ocular tissues. Female rats were previously found to be particularly sensitive to 2-Butoxyethanol. A group of eight female F344 rats (2 - 3 months old) were exposed by gavage to 250 mg of 2-Butoxyethanol/kg b.w. per day for 3 consecutive days and sacrificed 24 h after the last dose. Eight female rats received the dosing vehicle (water) and served as controls. At necropsy, petechial hemorrhages were noted on the sclera. Microscopic examination revealed treatment-related effects in the eyes, in addition to other known effects of BE exposure such as disseminated thrombosis and necrosis and infarction in various organs. The spectrum of histopathological changes noted in the eyes included hemorrhages localized in the posterior layers of the retina, leading to photoreceptor degeneration. Thrombi were identified in ciliary processes and limbal blood vessels. Histological changes suggestive of the retinal ischemic-infarctive process were also noted. Possible pathogenic mechanisms of 2-Butoxyethanol-induced retinopathy are discussed.
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disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2 Butoxyethanol
Toxicologic Pathology, 1999Co-Authors: Abraham Nyska, Robert R Maronpot, Philip H Long, Joseph H Roycroft, James R Hailey, Gregory S Travlos, Burhan I GhanayemAbstract:Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-Butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from ...
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Physiologically based pharmacokinetics of 2-Butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans
Toxicology and Applied Pharmacology, 1994Co-Authors: Richard A Corley, G.a. Bormett, Burhan I GhanayemAbstract:A physiologically based pharmacokinetic model was developed to describe the disposition of 2-Butoxyethanol (CAS 111-76-2) and its major metabolite, 2-butoxyacetic acid, in rats and humans. A previous human inhalation model by Johanson (Toxicol. Lett. 34, 23 (1986)) was expanded to include additional routes of exposure, physiological descriptions for rats, competing pathways for metabolism of 2-Butoxyethanol, and measured partition coefficients for 2-Butoxyethanol and 2-butoxyacetic acid. Simulations were compared to data gathered from rats following either intravenous infusion or oral or inhalation exposure and from humans following either inhalation or dermal exposure to 2-Butoxyethanol. It was necessary to add equations for both protein binding of 2-butoxyacetic acid in blood and saturable elimination of 2-butoxyacetic acid by the kidneys to consistently describe the data. While the model predicted that rats metabolize 2-Butoxyethanol and eliminate the acid metabolite faster per kilogram body weight than humans, the balance of these two processes in addition to physiological differences between species resulted in higher predicted peak blood concentrations as well as total areas under the blood concentration time curves for 2-butoxyacetic acid for rats versus humans. These species differences in kinetics coupled with the fact that human blood is significantly less susceptible than rat blood to the hemolytic effects of 2-butoxyacetic acid indicate that there is considerably less risk for hemolysis in humans as a result of exposure to 2-Butoxyethanol than would have been predicted solely from standard toxicity studies with rats.
Mark M Udden - One of the best experts on this subject based on the ideXlab platform.
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review of studies concerning the tumorigenicity of 2 Butoxyethanol in b6c3f1 mice and its relevance for human risk assessment
Journal of Toxicology and Environmental Health-part B-critical Reviews, 2004Co-Authors: Rodney J Boatman, Trevor Green, James E. Klaunig, Richard A Corley, Mark M UddenAbstract:The U.S. National Toxicology Program (NTP) has completed 2-yr inhalation exposures in rats and mice with 2-Butoxyethanol (BE). This review concerns the most significant findings from those studies and describes recent research into the mechanistic aspects of BE-mediated tumorigenesis in the mouse and the relevance of such effects to humans. Two tumor types were increased in B6C3F1 mice leading to the classification of “some evidence” of carcinogenicity: liver hemangiosarcomas in male mice and forestomach tumors in female mice (primarily benign papillomas). The results of research collected to date indicate that the tumorigenesis noted for BE was produced by indirect mechanisms. In particular, the occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition in this organ. Oral administration of BE in mice up to 600 mg/kg/d for up to 90 d produces a dose-related increase in iron (Perl’s staining) in Kupffer cells and hepatoc...
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rat erythrocyte morphological changes after gavage dosing with 2 Butoxyethanol a comparison with the in vitro effects of butoxyacetic acid on rat and human erythrocytes
Journal of Applied Toxicology, 2000Co-Authors: Mark M UddenAbstract:Rats exposed to 2-Butoxyethanol (2-BE) develop hemolysis preceded by red blood cell swelling and shape changes. In this study effects on red blood cell morphology of dosing rats with 2-BE by gavage were compared with the effects of incubation of rat erythrocytes in vitro with the principal metabolite of 2-BE, butoxyacetic acid (BAA). Morphology was assessed by bright-field and phase microscopy of Wright's stained blood smears and glutaraldehyde-fixed cells suspended in plasma or buffer. In vivo exposure to 2-BE resulted in stomatocytosis and spherocytosis in blood smears and cup-shaped cells and spherocytosis in the fixed samples. In vitro incubation with BAA produced erythrocytes with cup shapes, spherocytosis and red blood cell ghosts in fixed samples. The stomatocytes observed in the blood smears appear to be the morphological equivalents of the cup-shaped cells observed in fixed samples. A variable degree of echinocytosis was observed in blood smears from animals exposed to 2-BE and in the in vitro experiments with BAA. Stomatocytes, cup-shaped cells, and spherocytes are the principal morphological features of erythrocytes from rats exposed to 2-BE or in vitro exposure to BAA. In comparison, human red blood cells incubated with up to 2.0 mM BAA exhibited none of the morphological changes observed in rat erythrocytes. 2-Butoxyethanol in vivo and BAA in vitro cause similar changes in rat red blood cell morphology, adding further evidence to support the primary role of BAA in the hemolytic effect of 2-BE exposure in the rat.
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hemolysis and deformability of erythrocytes exposed to butoxyacetic acid a metabolite of 2 Butoxyethanol ii resistance in red blood cells from humans with potential susceptibility
Journal of Applied Toxicology, 1994Co-Authors: Mark M UddenAbstract:2-Butoxyethanol causes hemolysis in rodents but not in humans. 2-Butoxyethanol-induced hemolysis is primarily due to the effect of its metabolite 2-butoxyacetic acid (BAA). 2-Butoxyacetic acid did not cause hemolytic effects when incubated with blood from a limited number of normal individuals. Because 2-Butoxyethanol is contained in many consumer products, the possibility that there may be human subpopulations susceptible to hemolysis by BAA was examined. 2-Butoxyacetic acid was incubated with red blood cells from healthy young and older individuals and with red blood cells from patients with hereditary spherocytosis and sickle cell disease. After incubation of red blood cells with or without 2.0 mM BAA for up to 4 h, conditions that readily hemolyzed rat red blood cells, there was no increase in hemolysis or changes in mean cellular volume or morphology. The deformability of erythrocytes treated with BAA was also measured using a nuclepore filtration technique. No changes in deformability due to treatment with BAA were detected. Although BAA is a potent cause of hemolysis in rats, red blood cells in humans, including the elderly and patients with two disorders marked by chronic hemolysis, were not susceptible to BAA-induced hemolysis or loss of deformability.
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hemolysis and deformability of erythrocytes exposed to butoxyacetic acid a metabolite of 2 Butoxyethanol i sensitivity in rats and resistance in normal humans
Journal of Applied Toxicology, 1994Co-Authors: Mark M Udden, C S PattonAbstract:The effects of butoxyacetic acid (BAA), a metabolite of the important solvent 2-Butoxyethanol, on rat and human red blood cells (RBCs) were investigated. Rat RBCs demonstrated decreased deformability as assessed by a sensitive polycarbonate sieve filtration technique and an increased mean cellular volume after incubation with 0.2 and 2.0 mM BAA for 1-4 h. EvMuation of erythrocyte morphology showed that rat RBCs exposed to BAA became spherocytic and lysed to form erythrocyte membrane ghosts. Hemolysis of rat erythrocytes was rapid in 2.0 mM BAA. Changes in the deformability of rat erythrocytes appear to precede hemolysis. Treated rat erythrocytes also demonstrated a tendency to agglutinate and to release hemoglobin, which formed visible precipitates
Abraham Nyska - One of the best experts on this subject based on the ideXlab platform.
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age and dose sensitivities in the 2 Butoxyethanol f344 rat model of hemolytic anemia and disseminated thrombosis
Experimental and Toxicologic Pathology, 2007Co-Authors: Yuval Ramot, Shyamal D Peddada, Deborah A Lewis, Thomas L Ortel, Mike Streicker, Glenda J Moser, Susan A Elmore, Sandra M Ward, Abraham NyskaAbstract:Abstract In hemolytic disorders, such as sickle cell disease and β -thalassemia, the mechanisms of thrombosis are poorly understood. Appropriate animal models would increase the understanding of the pathophysiology of thrombosis. We previously reported that rats exposed to 2-Butoxyethanol (2-BE) developed hemolytic anemia and disseminated thrombosis resembling sickle cell disease and β -thalassemia. To characterize our model further, we investigated age- and dose-related differences in sensitivity to 2-BE. We exposed groups of 6- and 12-week-old F344 rats (5 animals/group) to 62.5, 125, and 250 mg/kg/day of 2-BE for up to 4 days. Blood was collected on days 2–4 for complete blood count and measurement of intracellular adhesion molecule-1 (ICAM-1). Histopathological evaluation was performed to find evidence of disseminated thrombosis. The maximum hemolytic response, resulting in decreased erythrocyte count and higher mean cell volume (MCV) occurred in the 12-week-old rats treated with the highest dose of 2-BE (250 mg/kg, p p
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2 Butoxyethanol female rat model of hemolysis and disseminated thrombosis x ray characterization of osteonecrosis and growth plate suppression
Toxicologic Pathology, 2005Co-Authors: Danielle N Lewis, Shay Shabat, Abraham Nyska, Kennita Johnson, David E Malarkey, Sandy Ward, Michael Streicker, Shyamal D Peddada, Meir NyskaAbstract:We recently proposed a chemically induced rat model for human hemolytic disorders associated with thrombosis. The objective of the present investigation was to apply a noninvasive, high-magnification X-ray analysis, the Faxitron radiography system, to characterize the protracted bone damage associated with this 2-Butoxyethanol model and to validate it by histopathology. Groups of female Fischer 344 rats were given 0, 250, or 300 mg of 2-Butoxyethanol/kg body weight daily for 4 consecutive days. Groups were then sacrificed 2 hours or 26 days after the final treatment. The treated animals displayed a darkened purple-red discoloration on the distal tail. Histopathological evaluation, including phosphotungstic acid-hematoxylin staining of animals sacrificed 2 hours after the final treatment, revealed disseminated thrombosis and infarction in multiple organs, including bones. The Faxitron MX-20 specimen radiography system was used to image selected bones of rats sacrificed 26 days posttreatment. Premature thinning of the growth plate occurred in the calcaneus, lumbar and coccygeal vertebrae, femur, and ilium of the treated animals. Areas of decreased radiographic densities were seen in the diaphysis of the femur of all treated animals. The bones were then examined histologically and showed a range of changes, including loss or damage to growth plates and necrosis of cortical bone. No thrombi were seen in the animals sacrificed at 30 days, but bone and growth plate changes consistent with prior ischemia were noted. The Faxitron proved to be an excellent noninvasive tool that can be used in future studies with this animal model to examine treatment modalities for the chronic effects of human thrombotic disorders.
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2-Butoxyethanol enhances the adherence of red blood cells
Archives of Toxicology, 2003Co-Authors: Alexander Koshkaryev, Meir Nyska, Nathan Ezov, Tal Levin-harrus, Meir Redlich, Felix Tsipis, Gregory Barshtein, Shay Shabat, Abraham Nyska, Saul YedgarAbstract:We recently presented a unique, chemically-induced rat model of hemolytic anemia and disseminated thrombosis. In this 2-Butoxyethanol (BE)-induced model the organs developing infarction are comparable to those seen in human diseases, characterized by hemolysis and thrombosis (e.g., thalassemia, sickle-cell disease, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome). Red blood cells (RBCs) have special flow properties, namely, self-aggregability, deformability, and potential adherence to endothelial cells (ECs) of the blood vessel wall, which are essential for adequate blood flow and tissue perfusion; their alteration facilitates circulatory disorders. To examine the possible contribution of alterations in RBC flow properties to the observed thrombosis in the present investigation we determined the BE-induced changes in adherence, aggregability, and deformability of RBCs from male and female Fischer F344 rats exposed to two, three, or four daily doses of BE at 250 mg BE/kg body weight. Control animals were treated with the vehicle alone. Blood was taken on days 2, 3, 4, and 29. The administration of BE did not affect the RBCs aggregability but markedly enhanced their adherence to extracellular matrix; such enhancement was correlated with adherence to cultured ECs. RBC/EC interaction has been shown to be a potent catalyst of vascular occlusion in hemolytic hemoglobinopathies; thus the enhanced RBC adherence to EC is a likely mechanism by which thrombosis and organ infarct are induced in BE-treated rats.
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dental pulp infarction in female rats following inhalation exposure to 2 Butoxyethanol
Toxicologic Pathology, 2000Co-Authors: Philip H Long, Burhan I Ghanayem, Robert R Maronpot, Joseph H Roycroft, Abraham NyskaAbstract:Female Fischer 344 (F344)/N rats (10 per exposure group) were exposed to 2-Butoxyethanol (BE) vapors (0, 31, 62.5, 125, 250, or 500 ppm 6 h/d, 5 d/wk, for 13 weeks) to characterize its prechronic toxicity. Dental lesions consisting of bilateral multifocal dental pulp thrombosis, pulp infarction, and odontoblast infarction were noted in the maxillary incisors of 3 of 4 rats from the 500-ppm group that were sacrificed when moribund during the first week of exposure. In addition, 1 rat from the 500-ppm group that was sacrificed on day 32 had similar unilateral incisor lesions but with additional findings consistent with a unilateral maxillary incisor fracture. In contrast, rats sacrificed after 13 weeks of exposure lacked dental lesions. In conclusion, BE has the potential to cause pulp thrombosis and odontoblast infarction in female rats. The apparent variability in response to BE noted in moribund sacrificed vs terminally sacrificed rats was attributed to development of tolerance to BE-induced hemolysis and subsequent incisor regeneration.
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ocular thrombosis and retinal degeneration induced in female f344 rats by 2 Butoxyethanol
Human & Experimental Toxicology, 1999Co-Authors: Abraham Nyska, R R Maronpot, Burhan I GhanayemAbstract:2-Butoxyethanol, used extensively for domestic and industrial purposes, was tested in our experiments for its potential to cause damage to female rat ocular tissues. Female rats were previously found to be particularly sensitive to 2-Butoxyethanol. A group of eight female F344 rats (2 - 3 months old) were exposed by gavage to 250 mg of 2-Butoxyethanol/kg b.w. per day for 3 consecutive days and sacrificed 24 h after the last dose. Eight female rats received the dosing vehicle (water) and served as controls. At necropsy, petechial hemorrhages were noted on the sclera. Microscopic examination revealed treatment-related effects in the eyes, in addition to other known effects of BE exposure such as disseminated thrombosis and necrosis and infarction in various organs. The spectrum of histopathological changes noted in the eyes included hemorrhages localized in the posterior layers of the retina, leading to photoreceptor degeneration. Thrombi were identified in ciliary processes and limbal blood vessels. Histological changes suggestive of the retinal ischemic-infarctive process were also noted. Possible pathogenic mechanisms of 2-Butoxyethanol-induced retinopathy are discussed.
Yoshikata Koga - One of the best experts on this subject based on the ideXlab platform.
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intermolecular interactions in 2 Butoxyethanol dmso h2o
The Journal of Physical Chemistry, 1996Co-Authors: Peter Westh And, Yoshikata KogaAbstract:Excess partial molar enthalpy, HBE, and chemical potential, μBE, of 2-Butoxyethanol (B) were determined in ternary mixtures of B, dimethyl sulfoxide (D), and H2O. The data were obtained in small enough mole fraction increments to evaluate the so-called interaction functions, ∂HBE/∂xB, ∂HBE/∂xD, ∂μBE/∂xB, and ∂μBE/∂xD. These interaction functions previously proved useful in elucidating the “mixing schemes” in binary aqueous solutions of B and D. For the binary mixtures, it was found that both B and D influenced H2O in the following manner: in the water-rich composition range (region I) within a certain threshold (xB < 0.0175 and xD < 0.28 at 25 °C), both solutes enhance the hydrogen-bonded network of water in their vicinity, and the mixtures retain the percolated nature of the network. At higher B or D concentrations (region II) a qualitatively different mixing scheme becomes operative. The results from this work suggest that, in the ternary mixtures, solute B and D influences the percolated hydrogen bond...
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Transition of the mixing scheme in the water-rich region of aqueous 2-Butoxyethanol : heat capacities and their temperature derivatives
Chemical Physics Letters, 1994Co-Authors: Peter Westh, Aase Hvidt, Yoshikata KogaAbstract:Abstract Weak jump anomalies were observed in the temperature derivatives of the heat capacities of aqueous 2-Butoxyethanol. The derivative, (∂ C p /∂ T ), is proportional to the third derivative of the Gibbs free energy with respect to T . The loci of these anomalies in the composition-temperature field fall on the boundary between two regions previously characterized by differences in the mixing scheme. Other third derivatives of free energy involving at least one composition differentiation showed peak anomalies at the same boundary.
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Transition of mixing scheme in the water-rich region of aqueous 2-Butoxyethanol: partial molar volumes and their derivatives
The Journal of Physical Chemistry, 1992Co-Authors: Yoshikata KogaAbstract:The mixing scheme boundary proposed in paper 1 (J. Phys. Chem. 1990, 94, 3879) was extended to high temperatures. Using the data of the excess partial molar volumes in aqueous solutions of 2-Butoxyethanol (BE), V m E (i) (i=BE or H 2 O), reported in paper 2 (J. Chem. Thermodyn., in press), the composition derivatives of V m E (BE), (∂V m (BE)/∂n BE ) nw , were calculated. n BE and n W are the amounts of BE and H 2 O in solution, respectively
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thermal expansivities of aqueous solutions of 2 Butoxyethanol in the water rich region transition of mixing scheme
Canadian Journal of Chemistry, 1992Co-Authors: James V Davies, Frankie W Lau, John T W Lai, Yoshikata KogaAbstract:Thermal expansivities of aqueous solutions of 2-Butoxyethanol (BE) were measured at concentrations of xBE < 0.04, where xBE is the mole fraction of BE. Thermal expansivity is a second derivative of the Gibbs free energy. The composition derivatives of thermal expansivities, the third derivatives, show peak anomalies at the same loci as the other third derivatives of the Gibbs free energy reported earlier from this laboratory (Can. J. Chem. 67, 671 (1989); J. Phys. Chem. 94, 3879 (1990); J. Phys. Chem. 95, 4119 (1991)). The loci of such anomalies form a boundary that separates two regions of totally different mixing schemes. The mixing scheme in the water-rich region seems to be consistent with the "iceberg formation," the "structure enhancement of H2O by hydrophobic solute," and the "hydrophobic attraction." In the intermediate composition region, the hydrogen bond network of H2O collapses due to the presence of too many molecules of BE, and H2O and BE molecules interact with each other as normal liquid m...
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Vapor pressures of aqueous 2-Butoxyethanol solutions at 25.degree.C: transitions in mixing scheme
The Journal of Physical Chemistry, 1991Co-Authors: Yoshikata KogaAbstract:The vapor pressures of aqueous solutions of 2-Butoxyethanol (BE) were determined at 25.00 o C. The partial pressures of BE and H 2 O and hence the excess partial molar free energies, G m E (i) (i=BE or H 2 O) were calculated by the Boissonnas method. Using the values of the excess partial enthalpies, H m E (i) (i=BE or H 2 O), measured previously in this laboratory the excess partial molar entropies, S m E (i) (i=BE or H 2 O), were calculated
