The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Gary O. Rankin - One of the best experts on this subject based on the ideXlab platform.
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Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-Chloroaniline in Fischer 344 rats.
Toxicology, 1998Co-Authors: Larry Dial, S R Kennedy, D K Anestis, Gary O. RankinAbstract:Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-Chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-Chloroaniline (0.5 or 1.0 mmol/kg; ∼50 μCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-Chloroaniline-derived radioactivity were primarily renally excreted with
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Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in Fischer 344 rats: comparisons with 2- and 4-Chloroaniline and 2- and 4-aminophenol.
Toxicology, 1996Co-Authors: Gary O. Rankin, Monica A. Valentovic, John G. Ball, D K Anestis, Kelly W. Beers, Derek W. Nicoll, Suk K. Hong, John L. Hubbard, Patrick I. BrownAbstract:Abstract Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2-chloroaniline or 4-Chloroaniline hydrochloride to Fischer 344 rats, but the nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The purpose of this study was to evaluate the in vivo and in vitro nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4-Chloroaniline and 2-chloroaniline. A comparison was also made between the nephrotoxic potential of the aminochlorophenols and the corresponding aminophenols to examine the effect of adding a chloride group on the nephrotoxic potential of the aminophenols. Male Fischer 344 rats (4/group) were given an i.p. injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg), an aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at 24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects than the parent chloroanilines in vivo. Also, 4-aminophenol was markedly more potent as a nephrotoxicant than 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino-5-chlorophenol induced only mild changes in renal function. In vitro, the phenolic compounds reduced p-aminohippurate accumulation by renal cortical slices at bath concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was required for the chloroanilines. However, all compounds reduced tetraethylammonium accumulation at bath concentrations of 0.1–0.5 mM or greater. These results indicate that extrarenally-produced aminochlorophenol metabolites do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol could result from an altered ability of the aminochlorophenol to redox cycle or form conjugates.
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In Vitro toxicity of 2- and 4-Chloroaniline: comparisons with 4-amino-3-chlorophenol, 2-amino-5-chlorophenol and aminophenols.
Toxicology in vitro : an international journal published in association with BIBRA, 1996Co-Authors: Monica A. Valentovic, John G. Ball, Suk-kil Hong, Bethany A. Rogers, M.k. Meadows, R.c. Harmon, Gary O. RankinAbstract:Abstract Chloroanilines have been associated with renal and hepatic toxicity. This study (a) examined the in vitro hepatic and renal toxicity of 2-chloroaniline and 4-Chloroaniline, (b) further examined whether aromatic ring hydroxylation would increase toxicity of the parent compound and (c) compared toxicity between respective aminochlorophenol and aminophenol. Renal and hepatic slices were exposed to varying concentrations of 2-chloroaniline, 4-Chloroaniline. 4-amino-3-chlorophenol, 2-amino-5-chlorophenol, 2-aminophenol or 4-aminophenol. Toxicity was monitored by measurement of pyruvate-directed gluconeogenesis and leakage of lactate dehydrogenase (LDH). Hepatic tissue was less susceptible to toxicity than kidney tissue for all compounds since LDH leakage was elevated only in renal tissue. Gluconeogenesis was reduced in renal cortical slices exposed to 0.1 μ m aminochlorophenols or 4-aminophenol, whereas a concentration of 0.5 μ m was necessary for the chloroanilines and 2-aminophenol. LDH release was increased in renal slices by aminochlorophenols and aminophenols but not by the chloroanilines. The nephrotoxic potential in renal cortical slices was 4-aminophenol> 2-amino-5-chlorophenol> 4-amino-3-chlorophenol> 2-aminophenol> 2-chloroaniline= 4-Chloroaniline. These results suggest that aromatic ring hydroxylation increased in vitro toxicity of the chloroanilines. Comparison of aminophenols with aminochlorophenols indicated that addition of a halogen can have variable effects on toxicity.
Thomas Braunbeck - One of the best experts on this subject based on the ideXlab platform.
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Toxicity of 4-Chloroaniline in early life stages of zebrafish (Danio rerio): II. Cytopathology and regeneration of liver and gills after prolonged exposure to waterborne 4-Chloroaniline.
Archives of environmental contamination and toxicology, 1999Co-Authors: Patricia Burkhardt-holm, Y. Oulmi, A. Schroeder, Volker Storch, Thomas BraunbeckAbstract:Ultrastructural alterations in liver and gills of embryonic and larval zebrafish (Danio rerio) following prolonged exposure to waterborne 0.05, 0.5, and 5 mg/L 4-Chloroaniline for up to 31 days as well as after a 14-day regeneration period were investigated by means of light and electron microscopy. Acute toxicity was also tested at 25 and 50 mg/L. Survival of zebrafish embryos and larvae was only impaired from 25 mg/L 4-Chloroaniline, but—after a transient stimulation following exposure to 0.5 mg/L—4-Chloroaniline hatching was retarded after exposure to ≥5 mg/L, and fish displayed increasing rates of abnormal development and pigmentation. In contrast, hepatocytes displayed a time- and dose-dependent response from 0.05 mg/L 4-Chloroaniline, including changes in nuclei, mitochondria, peroxisomes, endoplasmic reticulum, Golgi fields, lysosomes, and hepatic glycogen and lipid stores, as well as invasion of macrophages. In gills, dose-dependent effects were evident from 0.5 mg/L 4-Chloroaniline and included deformation of secondary lamellae due to vacuolization and desquamation of respiratory epithelial cells in conjunction with dilation of intercellular spaces. Respiratory epithelial cells displayed progressive mitochondrial changes, induction of cytoplasmic myelinated structures, augmentation of lysosomes, and modifications of Golgi fields. Erythrocytes were severely deformed. A 14-day regeneration period was sufficient for almost complete recovery of pathological symptoms in both liver and gills. Only minor volumetric changes in hepatocellular organelles and a limited number of myelinated bodies, lysosomes, and cytoplasmic vacuoles were reminiscent of prior 4-Chloroaniline exposure. In both qualitative and quantitative terms, most effects in hepatocytes after exposure of embryonic and larval zebrafish to waterborne 4-Chloroaniline are comparable to the reaction of hepatocytes in adult zebrafish liver after prolonged sublethal exposure as well as in larval zebrafish after microinjection. Morphological changes in erythrocytes indicate disturbance of respiration as an additional mode of action of 4-Chloroaniline.
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Toxicity of 4-Chloroaniline in early life-stages of zebrafish (Brachydanio rerio): I. cytopathology of liver and kidney after microinjection.
Archives of environmental contamination and toxicology, 1996Co-Authors: Y. Oulmi, Thomas BraunbeckAbstract:In addition to survival and hatching parameters, cytological alterations in liver and kidney of 4- and 6-d old zebrafish larvae (Brachydanio rerio) following single microinjection of fertilized eggs at the germ-ring stage with 5, 12.5, and 25 ng 4-Chloroaniline/egg were investigated by means of electron microscopy. Whereas survival remained unaffected, microinjection with 4-Chloroaniline disturbed hatching of larvae. Hatching was delayed by microinjection of 12.5 ng 4-Chloroaniline/egg and above when compared to controls. Cytological investigations revealed ultrastructural changes in both liver and kidney in a dose- and time-dependent fashion. In the liver, major cytopathological changes included fenestration, fragmentation, and vesiculation of the rough endoplasmic reticulum, proliferation of atypical mitochondria, and atypical lysosomes. Furthermore, myelin whorls, lipid inclusions, and cholesterol crystals were increased, whereas glycogen stores were reduced. Renal tubular cells displayed altered brush borders, proliferation of nucleoli, atypical mitochondria, fenestrated, fragmented, and vesiculated RER cisternae, as well as giant lysosomes. Most of these effects indicate cellular dysfunction (e.g., disturbance of lipid metabolism in the liver), whereas others illustrate general cellular stress-responses to chemical aggression. Comparisons of results with those of previous studies based on conventional fish exposure prove the suitability and sensitivity of microinjection bioassays with zebrafish eggs as an alternative to conventional early life-stage tests.
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Preexposure temperature acclimation and diet as modifying factors for the tolerance of golden ide (Leuciscus idus melanotus) to short-term exposure to 4-Chloroaniline.
Ecotoxicology and environmental safety, 1992Co-Authors: Thomas Braunbeck, Helmut SegnerAbstract:Abstract The influence of different temperature and nutrition regimes on the acute toxicity of 4-Chloroaniline to golden ide (Leuciscus idus melanotus) was investigated. Acute toxicity was determined over 48 hr at 20°C without feeding after a 2-day acclimation period. In an attempt to reveal underlying mechanisms accounting for diet- and temperature-related differences in the toxicant resistance of golden ide, biochemical and quantitative morphological parameters of the liver, a central organ in the xenobiotic metabolism of fish, were recorded throughout the 12-week acclimation period. In cold-acclimated fish, acute toxicity of 4-Chloroaniline was 40% higher than in fish acclimated to 20°C. If compared to 20°C, preacclimation to 14°C was characterized by a lower specific growth rate, an increase of hepatic glycogen, and a decrease of body and liver lipid deposits. The organelle composition of hepatocytes was not significantly altered by temperature acclimation. For the nutrition experiment, commercially available diets A and B of similar crude composition were used. Acute toxicity of 4-Chloroaniline was 60% lower with diet B than with diet A. If compared to diet B, diet A induced a higher specific growth rate and increased hepatocellular volume of endoplasmic reticulum and Golgi fields, whereas glycogen and lipid of the liver as well as body lipid contents were reduced. The toxicity of 4-Chloroaniline was correlated with the development of the endoplasmic reticulum, the major site of biotransformation enzymes. A consistent correlation with lipid contents could not be established. Results illustrate not only that assay conditions during the actual test may profoundly interact with results of toxicity studies, but also that maintenance conditions before the test can have significant consequences on results. In order to improve reproducibility of the results of acute toxicity tests, more consideration should be given to the standardization of pretest maintenance conditions of fish.
D K Anestis - One of the best experts on this subject based on the ideXlab platform.
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Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-Chloroaniline in Fischer 344 rats.
Toxicology, 1998Co-Authors: L D Dial, D K Anestis, S R Kennedy, G O RankinAbstract:Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-Chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-Chloroaniline (0.5 or 1.0 mmol/kg; approximately 50 microCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-Chloroaniline-derived radioactivity were primarily renally excreted with < 1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (micromol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-Chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-Chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-Chloroaniline and/or its metabolites in target tissue.
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Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-Chloroaniline in Fischer 344 rats.
Toxicology, 1998Co-Authors: Larry Dial, S R Kennedy, D K Anestis, Gary O. RankinAbstract:Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-Chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-Chloroaniline (0.5 or 1.0 mmol/kg; ∼50 μCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-Chloroaniline-derived radioactivity were primarily renally excreted with
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Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in Fischer 344 rats: comparisons with 2- and 4-Chloroaniline and 2- and 4-aminophenol.
Toxicology, 1996Co-Authors: Gary O. Rankin, Monica A. Valentovic, John G. Ball, D K Anestis, Kelly W. Beers, Derek W. Nicoll, Suk K. Hong, John L. Hubbard, Patrick I. BrownAbstract:Abstract Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2-chloroaniline or 4-Chloroaniline hydrochloride to Fischer 344 rats, but the nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The purpose of this study was to evaluate the in vivo and in vitro nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4-Chloroaniline and 2-chloroaniline. A comparison was also made between the nephrotoxic potential of the aminochlorophenols and the corresponding aminophenols to examine the effect of adding a chloride group on the nephrotoxic potential of the aminophenols. Male Fischer 344 rats (4/group) were given an i.p. injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg), an aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at 24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects than the parent chloroanilines in vivo. Also, 4-aminophenol was markedly more potent as a nephrotoxicant than 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino-5-chlorophenol induced only mild changes in renal function. In vitro, the phenolic compounds reduced p-aminohippurate accumulation by renal cortical slices at bath concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was required for the chloroanilines. However, all compounds reduced tetraethylammonium accumulation at bath concentrations of 0.1–0.5 mM or greater. These results indicate that extrarenally-produced aminochlorophenol metabolites do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol could result from an altered ability of the aminochlorophenol to redox cycle or form conjugates.
Patrick I. Brown - One of the best experts on this subject based on the ideXlab platform.
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Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in Fischer 344 rats: comparisons with 2- and 4-Chloroaniline and 2- and 4-aminophenol.
Toxicology, 1996Co-Authors: Gary O. Rankin, Monica A. Valentovic, John G. Ball, D K Anestis, Kelly W. Beers, Derek W. Nicoll, Suk K. Hong, John L. Hubbard, Patrick I. BrownAbstract:Abstract Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2-chloroaniline or 4-Chloroaniline hydrochloride to Fischer 344 rats, but the nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The purpose of this study was to evaluate the in vivo and in vitro nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4-Chloroaniline and 2-chloroaniline. A comparison was also made between the nephrotoxic potential of the aminochlorophenols and the corresponding aminophenols to examine the effect of adding a chloride group on the nephrotoxic potential of the aminophenols. Male Fischer 344 rats (4/group) were given an i.p. injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg), an aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at 24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects than the parent chloroanilines in vivo. Also, 4-aminophenol was markedly more potent as a nephrotoxicant than 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino-5-chlorophenol induced only mild changes in renal function. In vitro, the phenolic compounds reduced p-aminohippurate accumulation by renal cortical slices at bath concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was required for the chloroanilines. However, all compounds reduced tetraethylammonium accumulation at bath concentrations of 0.1–0.5 mM or greater. These results indicate that extrarenally-produced aminochlorophenol metabolites do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol could result from an altered ability of the aminochlorophenol to redox cycle or form conjugates.
G O Rankin - One of the best experts on this subject based on the ideXlab platform.
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Tissue distribution, subcellular localization and covalent binding of 2-chloroaniline and 4-Chloroaniline in Fischer 344 rats.
Toxicology, 1998Co-Authors: L D Dial, D K Anestis, S R Kennedy, G O RankinAbstract:Chloroanilines (CA) are widely used chemical intermediates which induce numerous toxicities including hematotoxicity, splenotoxicity, hepatotoxicity and nephrotoxicity. Although chloroaniline-induced hematotoxicity has been studied in detail, little information is available on the organ-directed toxicity seen following exposure to these agents. The purpose of this study was to examine and compare the excretion and distribution of two nephrotoxicant and hepatotoxicant chloroanilines (2- and 4-Chloroaniline) to liver, kidney, spleen, plasma and erythrocytes. Subcellular distribution and covalent binding in kidney and liver were also determined. Male Fischer 344 rats (four per group) were administered [14C]-2-chloroaniline or [14C]-4-Chloroaniline (0.5 or 1.0 mmol/kg; approximately 50 microCi/rat) intraperitoneally (i.p.). Urine, feces, blood and tissues were collected at 3 and 24 h. Both 2- and 4-Chloroaniline-derived radioactivity were primarily renally excreted with < 1% excretion in the feces by 24 h post-treatment. Both chloroanilines accumulated mainly in liver (percentage of administered dose/total tissue), but kidney generally had similar or higher equivalent concentrations (micromol/g tissue) compared to liver. Subcellular distribution revealed that for both chloroanilines, the cytosolic fraction generally had the highest level of radioactivity independent of time or dose. Covalent binding was detected in both liver and kidney, with the highest concentration (pmol/mg protein) of binding observed in the hepatic microsomal fraction regardless of compound, dose or time studied. In general, 2-chloroaniline derived radioactivity was excreted faster, reached peak tissue concentrations earlier, disappeared from tissues faster and had less covalent binding in target tissue at 24 h than 4-Chloroaniline-derived radioactivity. These results suggest that the increased toxic potential of 4-Chloroaniline as compared to 2-chloroaniline may be due in part to a more prolonged and persistent accumulation of 4-Chloroaniline and/or its metabolites in target tissue.
