Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Humans risk inadvertent intraperitoneal or intravenous exposure to formaldehyde (HCHO), commonly used for disinfection of implanted or extracorporeal medical devices. Various chemical and physical stresses are known to induce hepatic metallothionein. This study examined the effect of acute parenteral administration of HCHO on induction of hepatic metallothionein synthesis. Adult male CF1 mice were administered HCHO ip and hepatic metallothionein was quantified by the cadmium-radioassay method. HCHO (50 mg/kg) increased hepatic metallothionein as early as 8 hr after dosing with maximal levels (27-fold increase) occurring at 72 hr. Metallothionein concentrations were elevated (15-fold) 24 hr after 50 or 100 mg HCHO/kg but not at lower dosages. Concomitant elevations in hepatic zinc and copper content were observed. No increases in metallothionein were observed in kidney, pancreas, or intestine 24 hr after HCHO administration (100 mg/kg, ip). Induction of metallothionein by HCHO may reflect direct de novo synthesis since the response was abolished by pretreatment with the RNA synthesis inhibitor, actinomycin D. HCHO induction of metallothionein also does not appear to be mediated by stress-induced release of corticosteroids or catecholamines from the adrenal since the response was unaltered in adrenalectomized mice. Interference with the glutathione (GSH)-dependent oxidation of HCHO by reducing hepatic GSH concentrations to 40% of control after a 2-hr pretreatment with phorone decreased the metallothionein induction response to HCHO by 33%. This result suggests that the induction may be partially due to a HCHO metabolite, e.g., formate. Confirmation of metallothionein synthesis was obtained following spectral and chromatographic analysis. Thus, HCHO and/or a metabolite produces a marked increase in hepatic metallothionein and alters hepatic zinc and copper homeostasis, all of which are transient responses. Although HCHO was only mildly hepatotoxic at the highest dose (as evidenced by an increase in plasma alanine aminotransferase activity), such changes in metallothionein synthesis and essential metal homeostasis may be part of a cellular repair mechanism operant after acute toxic cell injury.
...
PMID:Acute exposure to formaldehyde induces hepatic metallothionein synthesis in mice. 271 95

In isolated, hemoglobin-free perfused livers of fasted rats, formaldehyde at an initial concentration of 10 mmol/l produced toxicity as evidenced by a release of enzymes (GPT, SDH) and of glutathione (mainly GSSG) into the perfusate, an accumulation of calcium in the liver, and a depletion of hepatic glutathione. Formaldehyde also led to an enhanced release of malondialdehyde into the perfusate, indicating peroxidative processes and decreased hepatic oxygen consumption by about 50-70%. The electron microscopic investigation of formaldehyde-exposed livers showed a destruction of the mitochondria (ruptured membranes, loss of the cristae) and some damage of the rough endoplasmic reticulum. Feeding the rats prior to surgery attenuated the hepatotoxic effects of 10 mmol/l formaldehyde. At an initial concentration of 3 mmol/l, formaldehyde did not release enzymes from livers of fed or fasted rats but only from those whose glutathione content had been depleted by treatment with phorone (250 mg/kg ip 2 h earlier). Formaldehyde liberated glucose and lactate from the livers of fed but not from those of fasted rats, indicating anaerobic energy supply in the fed state. The hepatotoxic action of formaldehyde is not due to its metabolism to formate or to the 10% methanol added as a stabilizing agent to the commercially available 37% solution named formalin. In conclusion, by destruction of mitochondria, formaldehyde inhibits aerobic energy supply and thereby presumably produces hepatocellular damage.
...
PMID:Mechanistic study on formaldehyde-induced hepatotoxicity. 275 59

Administration of large doses of acetaminophen or cocaine to male CD-1 mice produces significant hepatic injury with marked elevation in serum glutamate-pyruvate transaminase activity and severe hepatocellular necrosis. The proposed mechanism for this phenomenon is activation of both parent compounds to hepatotoxic metabolites. Ascorbic acid, 1 g/kg, given to mice 1 hour before and 1 hour after either acetaminophen or cocaine treatment prevented development of the severe hepatocellular damage observed with administration of either drug alone. Plasma disappearance of acetaminophen was less rapid in ascorbic acid-treated animals, suggesting that in vivo metabolism of acetaminophen was altered by ascorbic acid treatment. However, ascorbic acid treatment alone produced a modest decrease in hepatic glutathione content and did not prevent marked hepatic glutathione depletion when administered concomitantly with acetaminophen. Furthermore, a 2-mM ascorbic acid concentration did not alter in vitro hepatic microsomal metabolism of cocaine as measured by formaldehyde formation. While the mechanism(s) for its protective effect remains to be elucidated, these results raise the possibility that ascorbic acid may be useful in preventing hepatic injury caused by some hepatotoxic drugs.
...
PMID:Ascorbic acid protects against acetaminophen- and cocaine-induced hepatic damage in mice. 651 Feb 39

In vitro techniques make a major contribution to the development of alternatives to the in vivo "Draize" skin irritation test, and the development of sensitive and generally applicable in vitro endpoints of cutaneous toxicity is an area of intensive research. To investigate in vitro characteristics of cutaneous irritation, skin explants of rabbit and human origin were topically exposed to chemical irritants, after which the culture medium was analyzed for the presence of metabolites of both arachidonic and linoleic acid. In rabbits exposed to the potent irritant benzalkonium chloride, a direct relation was established between clinical signs of irritation and in vitro release of the proinflammatory mediator 12-hydroxyeicosatetraenoic acid (12-HETE) by the exposed skin. Histological examination revealed varying degrees of epidermal damage. 12-HETE was also the predominant hydroxy fatty acid released in a dose-dependent way by rabbit skin cultures after in vitro exposure to sodium dodecyl sulfate (SDS), benzalkonium chloride (BC), and formaldehyde (FA). Human skin cultures released, in addition to 12-HETE, predominantly 15-HETE and 13-hydroxyoctadecadienoic acid (13-HODE), omega-6 oxygenase products of arachidonic acid and linoleic acid, respectively. The irritant-induced release of hydroxy fatty acids was strongly inhibited by the lipoxygenase inhibitor eicosatetraynoic acid, indicating enzyme-mediated generation of these bioactive lipids. Comparison of hydroxy fatty acid release to more established markers of cytotoxicity (leakage of the cellular enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH)) revealed that increased levels of 13-HODE, 9-HODE, 12-HETE, and ALT were specific markers of cutaneous irritancy in rabbit skin cultures.
...
PMID:Release of arachidonic and linoleic acid metabolites in skin organ cultures as characteristics of in vitro skin irritancy. 760 24

The effects of formaldehyde (F), m-cresol (C), guaiacol (G), ethanol (E) and their mixture (FC, FCE, FG, FGE) on erythrocytes and isolated hepatocytes from rats and surface tension in water were examined. Hypotonic hemolysis of erythrocytes was inhibited by m-cresol, while guaiacol, formaldehyde and ethanol accelerated the hemolysis. Lower concentrations of the mixture inhibited hypotonic hemolysis, but higher concentrations accelerated hemolysis. Formaldehyde caused a decrease of transaminase (GOT, GPT) in the medium and hepatocytes. GOT and GPT in the medium were increased by m-cresol, but those in the hepatocyte were decreased by this agent. FC and FCE at 10 mM increased GOT in the medium, but FG and FGE decreased GOT. All mixtures decreased GOT and GPT in hepatocytes and GPT in the medium. All mixtures and formaldehyde inhibited GOT and GPT activity. Formaldehyde and m-cresol decreased hepatocyte viability. In the all mixtures-added hepatocytes, the viability was markedly lowered. Formaldehyde, m-cresol, guaiacol and ethanol caused a depression of surface tension, but the depressive effects of FG and FGE were weaker than that of guaiacol. These results suggest that the observed effects of the drug mixtures on erythrocytes and hepatocytes were the additive effects of the component drugs.
...
PMID:[Effects of disinfectants on erythrocytes and isolated hepatocytes from rats and surface tension]. 833 Aug 3

The liver synthesizes prokallikrein and is the main organ to clear the active enzyme (plasma-kallikrein) from circulation. This clearance, a receptor-mediated endocytosis, is calcium-independent and not affected by the blockade of Kupffer cells. The effects of endothelial cells blockade and of acetaminophen intoxication on the clearance of 10 nM rat plasma-kallikrein (RPK) by the isolated, exsanguinated and perfused rat liver are now reported. Endothelial cells blockade obtained by the addition of large excess (30 uM) of formaldehyde-treated serum albumin to the perfusion fluid does not affect the hepatic clearance of RPK (the half-lives of hepatic uptake were 15.5 +/- 1.0 min in the absence versus 16.5 +/- 1.4 min in the presence of the treated protein, p > 0.05). Some livers were perfused 24 hours after acetaminophen intoxication: 6.6 mmol/kg given i.p. after a 42-hour period of fast. Hepatocyte injury suggested by elevated aminotransferase activity (ALT 10 times control value, AST 30 times control value), acute phase inflammatory response (serum alpha 2-macroglobulin increase) and reduced synthetic function (serum albumin decrease), was confirmed histologically and only zone 3 hepatocytes were necrotic. A 66-hour period of fast does not affect by itself the hepatic clearance of RPK (16.9 +/- 1.3 min of half-life of hepatic uptake) when compared with the control group (15.5 +/- 1.0 min, p > 0.05). On the other hand the RPK clearance by the livers of rats previously intoxicated with acetaminophen was markedly deficient (the half-life of hepatic uptake was 39.2 +/- 3.2 min). These findings suggest that RPK is internalized by hepatocytes, preferentially by those of the perivenular zone of the hepatic acinus.
...
PMID:Plasma-kallikrein clearance by the liver of acetaminophen-intoxicated rats. 846 45

Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg(-1)). Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured. Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group. The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication.
...
PMID:Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication. 1086 43

Isobutyraldehyde, a branched alkyl aldehyde, is used as a chemical intermediate and flavoring agent. It was nominated by the National Cancer Institute for toxicity and carcinogenicity studies by the NTP. Reasons for nomination and selection of isobutyraldehyde for study included its high potential for human exposure as suggested by its high production volume, its use as a chemical intermediate and food flavoring agent, suspicion of carcinogenicity due to an increased incidence of cancer at an aldehyde manufacturing plant where workers were exposed to a variety of aldehydes, its structural relationship to formaldehyde (a nasal carcinogen in rats), and the lack of toxicity and carcinogenicity studies on isobutyraldehyde in animals. Although human exposure occurs orally, dermally, or via inhalation, the inhalation route of exposure was selected for these animal studies because of the instability of isobutyraldehyde in water and feed. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyraldehyde (approximately 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells; in vivo tests were conducted in Drosophila melanogaster germ cells and bone marrow cells of rats and mice. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days a week, for 13 weeks. All rats exposed to 8,000 ppm died before the end of the study. Three male rats and six female rats in the 4,000 ppm groups and one female in the 500 ppm group died before the end of the study. The final mean body weight of male rats in the 4,000 ppm group and the body weight gains of 4,000 ppm males and females were significantly less than those of the chamber controls. Clinical findings in rats exposed to 4,000 or 8,000 ppm included abnormal respiratory sounds, decreased activity, nasal discharge, prostration, and slowed respiration. A minimal mature neutrophilia, evidenced by increased segmented neutrophil numbers, occurred in exposed groups of male and female rats. Exposure to isobutyraldehyde resulted in minimal increases in alanine aminotransferase activity in all groups of male and female rats. Spermatozoal motility in 500 and 1,000 ppm males was significantly reduced and females exposed to 4,000 ppm differed significantly from the chamber control females in the relative time spent in the estrous stages. No gross lesions were observed at necropsy that could be associated with isobutyraldehyde exposure. In the 8,000 ppm groups, severe necrosis of the epithelium, and occasionally of the entire mucosa, of the nasal turbinates accompanied by an acute inflammatory reaction was observed. Increased incidences of squamous metaplasia and mild acute inflammation occurred in male and female rats exposed to 4,000 ppm. Minimal to mild degeneration of the olfactory epithelium was observed in all male rats in the 2,000 and 4,000 ppm groups. Male rats exposed to 4,000 or 8,000 ppm and females exposed to 4,000 ppm had mild osteodystrophy of the turbinate bone. The incidences of necrosis/degeneration of the larynx and trachea were increased in male rats in the 8,000 ppm group. The incidences of mild to moderate lymphoid depletion of the spleen and thymus and lymphoid necrosis of the thymus were significantly increased in male and female rats exposed to 8,000 ppm. 13-WEEK STUDY IN MICE: Ten male and 10 female B6C3F1 mice were exposed to 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 13 weeks. One male in the chamber control group, one male in the 1,000 ppm group, nine males and all females in the 4,000 ppm groups, and all males and females in the 8,000 ppm groups died before the end of the study. The final mean body weight and body weight gain of female mice in the 1,000 ppm group were significantly less than those of the chamber controls. Clinical findal findings included decreased activity, tremors, prostration, and slower and labored respiration. The absolute and relative kidney weights of males in the 1,000 and 2,000 ppm groups were significantly increased. There were no gross lesions observed at necropsy that could be associated with isobutyraldehyde exposure. Histopathologically, the nasal cavity and lymphopoietic tissues were considered target organs, with changes similar, but not identical, to those observed in rats. Increased incidences of nonneoplastic lesions of the nasal cavity were observed in male and female mice exposed to 1,000 ppm or greater. These lesions included necrosis, inflammation, hyperplasia, and squamous metaplasia of the epithelium; serous and suppurative exudate within the nasal passages; olfactory epithelial degeneration; and osteodystrophy of the turbinate bone. Mild to moderate lymphoid depletion and/or lymphoid necrosis were observed in the thymus of male and female mice exposed to 8,000 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 500, 1,000, or 2,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 105 weeks Survival, Body Weights, and Clinical Findings No differences in survival rates between exposed and chamber control rats were found. The mean body weights of male and female rats were generally similar to those of the chamber controls throughout the study. Pathology Findings No increase in neoplasm incidences that could be attributed to exposure to isobutyraldehyde was observed in male or female rats. Nonneoplastic lesions related to isobutyraldehyde exposure were limited to the nose and consisted of squamous metaplasia of the respiratory epithelium, degeneration of the olfactory epithelium, and suppurative inflammation. Incidences of minimal to mild squamous metaplasia in 1,000 and 2,000 ppm males and females and in 500 ppm females were significantly greater than those in the chamber controls. Another lesion associated with isobutyraldehyde exposure was minimal to mild degeneration of the olfactory epithelium in 2,000 ppm males and females. The incidences of suppurative inflammation (rhinitis) in male and female rats exposed to 2,000 ppm were increased compared to the chamber controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 500, 1,000, or 2,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings There was an exposure-related decrease in survival of male mice, and the survival of males exposed to 2,000 ppm was marginally lower than that of the chamber controls. The mean body weights of female mice exposed to 1,000 or 2,000 ppm were lower than those of the chamber controls during the second year of the study. Pathology Findings No neoplasms that could be attributed to iso butyraldehyde exposure were observed in mice. Non neoplastic lesions related to isobutyraldehyde exposure were limited to the nose. The incidences of olfactory epithelial degeneration in 1,000 and 2,000 ppm males and females were significantly greater than in the chamber controls. GENETIC TOXICOLOGY: Isobutyraldehyde is mutagenic in vitro and in vivo, with the strongest responses observed in mammalian cell assays that measured chromosomal damage. Results of an initial mutagenicity test in S. typhimurium were negative; a second test, con ducted with different strains and varying concentrations of induced S9 activation enzymes, gave equivocal results. Strongly positive responses were obtained in the mouse lymphoma assay for mutation induction in L5178Y cells without S9 and in cytogenetic tests for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Sister chromatid exchanges were significantly increased with and without S9, but induction of chromosomal aberrations was noted unequivocally only in the absence of S9. No induction of sex-linked recessive lethal mutations was observed in germ cells of male D. melanogaster administered isobutyraldehyde by feeding or by injection. In vivo, isobutyraldehyde was demonstrated to induce chromosomal aberrations in bone marrow cells of male mice, but no increases in micronuclei were observed in bone marrow cells of mice or rats after administration of isobutyraldehyde. All these in vivo cytogenetic studies used doses that reached lethality CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of isobutyraldehyde in male or female F344/N rats or male or female B6C3F1 mice exposed to 500, 1,000, or 2,000 ppm isobutyraldehyde. In male and female rats, exposure to isobutyraldehyde induced squamous metaplasia and suppurative inflammation of the nasal respiratory epithelium and degeneration of the nasal olfactory epithelium. In male and female mice, exposure to isobutyraldehyde caused degeneration of the nasal olfactory epithelium. Synonyms: Dimethylacetaldehyde; 2-formylpropane; isobutanal; isobutylcarboxaldehyde; isobutyral; isobutyric aldehyde; isobutyrylaldehyde; isopropylformaldehyde; 2-methylpropanal; 2-methyl-1-propanal; a-methylpropionaldehyde; 2-methylpropionaldehyde; valine aldehyde
...
PMID:NTP Toxicology and Carcinogenesis Studies of Isobutyraldehyde (CAS No. 78-84-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 1

C.I. Direct Blue 218 is a copper chelated dye used for cellulose, acetate, nylon, silk, wool, tissue, papers, and textile goods with a urea-formaldehyde finish. C.I. Direct Blue 218 is one of five chemicals/dyes that are part of the National Toxicology Program's Benzidine Dye Initiative, established to determine the toxicity and carcinogenicity of representative benzidine congeners, congener-derived dyes, and benzidine-derived dyes. Industrial grade C.I. Direct Blue 218 was selected for study because of its widespread use. Because of the high salt content, the dye was desalted prior to use. Toxicology and carcinogenesis studies were conducted by administering C.I. Direct Blue 218 in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All rats survived until the end of the study. Rats receiving 30,000 ppm lost weight, and the mean body weight gain of males receiving 15,000 ppm was significantly lower than that of the controls. Feed consumption by rats receiving 30,000 ppm was lower than that by the controls. Decreased organ weights at the 30,000 ppm level were related to the decreased body weights at this exposure level. 14-DAY STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All mice survived until the end of the study. The final mean body weight of males receiving 30,000 ppm was 25% lower than that of controls and that of 30,000 ppm females was 20% lower than that of controls. Feed consumption by exposed and control groups was similar except for the 15,000 and 30,000 ppm groups. Feed spillage, due to reduced palatability, precluded the accurate determination of feed consumption by these two groups. Male and female mice receiving 30,000 ppm appeared hyperactive and emaciated during the last week of the study. Decreased organ weights were noted at 30,000 ppm and were attributed to the decreased mean body weights at this exposure level. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. All male and female rats survived until the end of the study. Rats exposed to 3,000,10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 200, 600 or 1,300 mg dye/kg body weight (males) and 200, 800, or 1,400 mg/kg (females). The final mean body weight of male rats receiving 20,000 ppm was 24% lower than that of the controls and the final mean body weight of female rats receiving 20,000 ppm was 15% lower than that of the controls. Feed consumption by exposed and control groups was similar except in the 20,000 ppm groups where feed spillage was noted. Absolute and relative kidney weights of rats receiving 10,000 or 20,000 ppm were significantly greater than those of controls. Significantly decreased organ weights were noted, particularly in the 20,000 ppm groups, and were attributed to the lower mean body weights at this exposure level. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in male and female rats receiving 10,000 and 20,000 ppm were significantly lower than those of controls. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 20,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular injury. Male rats receiving 10,000 ppm and male and female rats receiving 20,000 ppm had hepatic lesions consisting of intracytoplasmic pigment in periportal Kupffer cells, minimal to mild individual hepatocyte necrosis, increased numbers of binucleated and multinucleated hepatocytes, and minimal bile duct hyperplasia. Male and female rats receiving 20,000 ppm had ys receiving 20,000 ppm had yellow-green pigment within the cytoplasm of proximal convoluted tubules of the kidney. Microconcretions of mineral were observed along the corticomedullary junction of the kidney in most female rats, but the numbers of microconcretions in kidney sections were increased in females that received 20,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. There were no deaths attributed to C.I. Direct Blue 218. Mice exposed to 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 400, 1,500, or 3,600 mg dye/kg body weight (males) and 400, 1,800, or 4,000 mg/kg (females). The final mean body weight of males that received 20,000 ppm was 24% lower than that of the controls, and the final mean body weight of females that received 20,000 ppm was 14% lower than that of controls. Feed consumption by exposed mice was similar to that by controls except in the 20,000 ppm groups where feed spillage was noted. Significant differences in organ weights were noted at 20,000 ppm which were attributed primarily to the lower mean body weights in these exposure groups. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte volume, and mean erythrocyte hemoglobin values were significantly lower in males and females receiving 10,000 and 20,000 ppm. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female mice receiving 10,000 and 20,000 ppm were significantly higher than those of controls, indicating hepatic injury. Male and female mice receiving 20,000 ppm had hepatic lesions consisting of centrilobular hepatocyte hypertrophy and karyomegaly, multifocal individual hepatocyte necrosis, oval cell proliferation, and periportal Kupffer cells with intracytoplasmic pigment. Males and females receiving 20,000 ppm also had increased numbers of pigmented macrophages within the red pulp of the spleen. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of C.I. Direct Blue 218 were based on the lower final mean body weights and the occurrence of hepatic lesions in the 20,000 ppm groups in the 13-week study. Groups of 60 male and 60 female rats were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 rats from each group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of female rats receiving 10,000 ppm was slightly, but not significantly, lower than that of the controls. Mean body weights of male and female rats in the 10,000 ppm groups were approximately 5% to 14% lower than those of the controls after week 15, and the final mean body weights of male and female rats at this level were 11% and 9% lower than those of the controls, respectively. Feed consumption by exposed male and female rats was similar to that by the controls and was estimated to deliver daily doses of 40, 120, and 440 mg dye/kg body weight to males and 50, 140, and 470 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in 10,000 ppm female rats were significantly lower than those of controls, while in males only the mean erythrocyte hemoglobin value was significantly lower. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 10,000 ppm were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: Squamous cell papillomas of the oral mucosa (pharynx) occurred in five males receiving 10,000 ppm but not in the lower exposure groups or in controls. A squamous cell carcinoma occurred in one 10,000 ppm male and a benign basosquamous tumor was observed in another. The incidence of oral mucosal neoplasms in the 10,000 ppm males was significantly greater than that in controls and exceeded the range observed in untreated historical controls (lO/l,253, 0.8%; range 0%-4%). These neoplasms were considered chemical related. Administration of C.I. Direct Blue 218 to rats produced significantly increased incidences of forestomach basal cell hyperplasia in males receiving 3,000 or 10,000 ppm (0 ppm, 0/50; 1,000 ppm, 2/50; 3,000 ppm, 10/50;10,000 ppm, 19/50) and in females receiving 10,000 ppm (1/50, 1/49, 5/50, 11/49). Further, there were marginal increased incidences of focal squamous hyperplasia in the 3,000 and 10,000 ppm males (1/50,1/50, 6/50, 4/50). Squamous cell papillomas of the forestomach were seen in two 3,000 ppm males and in one 10,000 ppm male; no papillomas were observed in the controls. A squamous cell carcinoma was also seen in one 3,000 ppm male. Because of the uncommon occurrence of forestomach neoplasms in untreated control male rats (4/1,253, 0.3%; range 0%-2%) and the slight increase in the incidence of focal hyperplasia, these neoplasms may have been chemical related. The incidence of uterine endometrial stromal polyps in each exposed group of female rats was significantly greater than that of the controls (1/50,12/50,10/50, 10/50). Because the incidences in the exposed groups did not increase in a dose-related manner and the incidence in the controls was unusually low (historical incidence: 205/1,251,16.4%; range 2%-30%), the higher incidence of stromal polyps in the exposed groups was not considered chemical related. 2-YEAR STUDY IN MICE: The dose selection for the 2-year study was based on the lower final mean body weights and the liver lesions observed at the 20,000 ppm level in the 13-week study. Groups of 60 male and 60 female mice were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls. Mean body weights of male and female mice receiving 10,000 ppm were 10% to 29% lower than those of the controls during most of the study, and the final mean body weights in these groups were 19% lower than that of the controls for males and 27% lower than that of the controls for females. Feed consumption by exposed mice was similar to that by controls and the diets were estimated to deliver daily doses of approximately 120, 360, and 1,520 mg of dye/kg body weight to males and 140, 470, and 2,050 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: Hematocrit, hemoglobin, and mean erythrocyte volume values in males and females receiving 10,000 ppm were significantly lower than those of the controls. Serum levels of alanine aminotransferase and/or sorbitol dehydrogenase values in male and female mice that received 10,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular damage. Pathology Findings: The administration of C.I. Direct Blue 218 to mice produced significantly increased incidences of hepatocellular adenoma (0 ppm, 16/50; 1,000 ppm, 19/50; 3,000 ppm, 17/50; 10,000 ppm, 40/50) and hepatocellular carcinoma (7/50, 3/50, 8/50,17/50) in males receiving 10,000 ppm, and a significantly increased incidence of hepatocellular adenoma in females receiving 3,000 or 10,000 ppm (7/49, 12/50, 17/49, 41/49). In females that received 10,000 ppm, the incidence of hepatocellular carcinoma was marginally increased. Consistent with these findings, the incidence of hepatocellular foci of cytologic alteration, a preneoplastic lesion, was also increased in males and females in the 10,000 ppm groups. The increased incidences of hepatocellular foci, adenomas, and carcinomas were considered chemical related. Uncommon renal tubule neoplasms also occurred at low incidences in male mice receiving C.I. Direct Blue 218, but not in controls. Renal tubule adenomas were seen in two males receiving 1,000 ppm, one male receiving 3,000 ppm, and one male receiving 10,000 ppm. A renal tubule carcinoma was also seen in one male that received 1,000 ppm. Because renal tubule neoplasms are uncommon in male mice (4/1,366, 0.3%; range 0%-2%), these neoplasms may have been chemical related. Carcinomas of the small intestine occurred in four male mice receiving 10,000 ppm. One was observed at the 15-month interim evaluation, while the other three were observed in mice at the end of the study. One control male mouse also had a carcinoma of the small intestine. Because of the uncommon occurrence of small intestine neoplasms in untreated male mice (12/1,374, 0.9%; range 0%-4%), the slightly higher incidence of these neoplasms in males receiving 10,000 ppm may have been chemical related. Carcinomas of the small intestine also occurred in one 3,000 ppm and one 10,000 ppm female, but the low incidences precluded drawing an association with chemical administration. GENETIC TOXICOLOGY: C.I Direct Blue 218 was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 tested with and without exogenous metabolic activation (S9). It was also tested in a modified Salmonella test protocol which employed reductive metabolism supplied by flavin mononucleotide or rat cecal bacteria, followed by oxidative metabolism; results of this test using strain TA1538 were also negative. C.I. Direct Blue 218 induced a small but significant increase in sister chromatid exchanges in Chinese hamster ovary cells at the highest dose tested without S9. No increase in chromosomal aberrations were observed in Chinese hamster ovary cells with or without S9. C.I. Direct Blue 218 did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Direct Blue 218 in male F344/N rats based on the occurrence of pharyngeal neoplasms. Squamous cell neoplasms of the forestomach may have been chemical related. There was no evidence of carcinogenic activity of C.I Direct Blue 218 in female F344/N rats given 1,000, 3,000, or 10,000 ppm. There was clear evidence of carcinogenic activity of C.I. Direct Blue 218 in male and female B6C3F1 mice based on increased incidences of hepatocellular adenomas and carcinomas. The occurrence of a few neoplasms of the kidney and small intestine in male mice may have been related to C.I. Direct Blue 218 treatment. The administration of C.I. Direct Blue 218 produced an increased incidence of forestomach basal cell hyperplasia in rats and hepatocellular foci of cytologic alteration in mice. Synonyms: cuprate(4-), [mu-[(3,3'-dihydroxy[1,1'-biphenyl]-4,4'-diyl)bis[5-amino-4-hydroxy- 2,7-naphthalnedisulfonato]](8-)]]di-, tetrasodium; copper, [tetrahydrogen-3,3'-[(3,3'-dihydroxy-4,4'-biphenylylene)bis(azo)]bis [5-amino-4-hdroxy-2,7-naphthalenedisulfonato](4-)]di-, tetrasodium salt; 1-naphthol-3,6-disulfonic acid, 2,2'-(3,3'-dihydroxy-4,4'-biphenylylenebisazo)bis [8-amino-, dicopper deriv., tetrasodium salt
...
PMID:NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 218 (CAS No. 28407-37-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 1

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants. This study compared effects of two PCB mixtures, Aroclors 1221 (A1221) and 1254 (A1254) on serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, creatinine and uric acid in female rats. Histopathological changes in the liver and kidney were also examined. A group of adult Wistar rats served as controls. Groups II and III were subcutaneously injected with A1221 and A1254 at 10 mg/kg every other day for 6 weeks. At the end of this period, all animals were decapitated and blood samples were collected. Serum urea, creatinine, uric acid, ALT, AST and ALP levels were determined. Liver and kidney were collected for histopathological examination. They were fixed in formaldehyde and processed for light microscopy. Both A1221 and 1254 significantly elevated serum ALT (p < 0.05) and AST (p < 0.01) levels compared to the control group. Serum ALP values were significantly increased by A1221 (p < 0.05), but they were unaffected in the A1254 group. Treatment with both A1221 and A1254 significantly increased serum levels of urea (p < 0.05), creatinine (p < 0.01) and uric acid (except in the A1221 group; p < 0.005). Distinct histopathological changes including renal corpuscular atrophy, peritubular vascular congestion and dilated cortical tubules, sinusoidal dilatation, congestion and mononuclear cell infiltration were observed. These findings suggest that PCBs may cause nephrotoxicity and hepatotoxicity in female rats.
...
PMID:Comparative evaluation of hepatotoxic and nephrotoxic effects of aroclors 1221 and 1254 in female rats. 1618 Feb 46


1 2 3 Next >>

---