UMLS:C0002871 - FACTA Search

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Query: UMLS:C0002871 (anemia)
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Hyperplasia of Brunner's glands is a rare phenomenon. It may cause obstructive symptoms, anemia or the patient may be totally asymptomatic. The diagnosis can be confirmed with endoscopic examination and upper gastrointestinal series. The surgical treatment or hyperplasia of the Brunner's glands should be conservative since the lesion is not premalignant. If complications do occur, local excision is the treatment of choice. Two patients are reported who had Brunner gland hyperplasia as an incidental finding at exploration for pancreatic pseudocyst, and a brief review of the literature is made.
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PMID:Hyperplasia of Brunner's glands of the duodenum. 85 Dec 97

A rare case of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL) associated with chronic renal failure was described in this report. A 73-year-old male was admitted and diagnosed as IPL. IPL is proposed by Mori et al. in 1980. Clinical entity of IPL is (1) Polyclonal hyperimmunoglobulinemia (2) Systemic Lymphadenopathy characterized by remarkable mature plasmacytosis without atypism and by no destruction of the structures. (3) All disease with polyclonal hyperimmunoglobulinemia can be excluded. In this patient, physical findings showed enlarged lymph nodes (1-2 cm) in bilateral nuchal, submandibular, axillary and inguinal lesions. Laboratory examinations showed polyclonal hyperimmunoglobulinemia (especially IgG, IgA), anemia and renal dysfunction. Microscopic observation of hematoxylin-eosin staining in the axillary lymph node showed increased mature plasma cells without evidence of malignant growth. Immunoperoxidase staining showed intracytoplasmatic polyclonal immunoglobulins. IPL is known as invading other organs besides lymph node, for example skin, lung or kidney. This patient showed renal dysfunction (Cr clearance 11 ml/min, severe proteinuria). Nine cases of IPL and multicentric plasma cell type Giant Lymphnode Hyperplasia (GLH) concurrent with renal dysfunction were reported. Only in two of them chronic renal failure were reported. Twice a week hemodialysis improved his condition and laboratory findings.
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PMID:[A case of idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia associated with chronic renal failure]. 228 6

Mice infected with Trypanosoma musculi developed hyperplasia of the spleen, lymph nodes, and liver; in contrast, their thymuses displayed transient involution. All organs returned to normal in a month or less. There was modest anemia, lasting until the parasites were cleared from the bloodstream, followed by a rapid influx of erythrocytes into the blood and a subsequent return to normal erythrocyte numbers. During the first 2 weeks, trypanosomes and trypanosome-derived substances were found in the livers and, in moderate amounts, in the red pulp of the spleens; thereafter, trypanosomes and trypanosome-derived substances gradually decreased in these organs. The lymphoreticular hyperplasia involved a large increase of immunoglobulin G (IgG)-containing cells in the spleens and lymph nodes at 2 weeks of infection. Hyperplasia of immunoglobulin-producing cells correlated with elevation of serum immunoglobulins, especially IgG. Cells producing IgG in the spleens proliferated mainly around the central arterioles of the white pulp, i.e., in the T-cell-dependent areas. The decline of trypanosome-derived substances in the livers and spleens was associated with marked hyperplasia of IgG-containing cells in the spleens and lymph nodes. These results suggest that trypanosome-mediated depression of murine immune responses is attributable to proliferation and terminal differentiation of more-mature lymphoid cells and temporary inhibition of normal maturation of less-mature precursor cells.
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PMID:Histopathological and immunocytochemical studies of Trypanosoma musculi infection of mice. 733 60

The effects of acute poisoning by cupric sulfate in a number of species are well known; however, the effects of chronic low-level ingestion of cupric sulfate are less well characterized. Because exposure of humans to cupric sulfate may occur through drinking water, food, soil, or ambient air, subchronic toxicity studies were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week exposure) and dosed feed (2- and 13-week exposure) routes. Animals were evaluated for histopathology, clinical pathology, reproductive toxicity, and tissue metal accumulation, and target organs were examined by a variety of special stains and by electron microscopy to characterize the observed lesions. In drinking water, cupric sulfate concentrations of 300 to 100 ppm produced no ill effects, whereas concentrations of 3000 to 30,000 ppm were lethal to rats and mice within 2 weeks. In feed, cupric sulfate concentrations of 4000 to 16,000 ppm caused significant reductions in body weight gain in both species in the 2- and 13-week studies. Hyperplasia and hyperkeratosis of the limiting ridge of the forestomach were present in both species in the 2- and 13-week studies. Rats in the dosed feed studies had a dose-related increase in inflammation in the liver and changes in clinical chemistry parameters which were indicative of hepatocellular damage and cholestasis. Histologic changes in the kidneys of rats consisted of a dose-related increase in the number and size of eosinophilic protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. Droplets were larger and more numerous in males than in females. Urinalysis results were suggestive of renal tubular epithelial damage. Iron staining of spleens from treated animals indicated a marked depletion of iron stores in both male and female rats, but not in mice, while hematologic and clinical chemistry alterations in rats in the 13-week study, along with histologic changes in bone in the 2-week dosed feed study, were indicative of a microcytic anemia. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. These results indicate that cupric sulfate at high exposure levels is a hepatic and renal toxicant, as well as an inducer of anemia in rodents, with rats more sensitive than mice following subchronic exposure.
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PMID:Subchronic toxicity of cupric sulfate administered in drinking water and feed to rats and mice. 825 99

The toxicity of 3,3',4,4'-tetrachloroazobenzene (TCAB) was evaluated in 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical chemistry, hematology, thyroid hormone analyses, and reproductive parameters. Groups of 10 rats and 10 mice of each sex were exposed to TCAB at dose levels of 0, 0.1, 1, 3, 10, or 30 mg/kg for 5 days a week for 13 weeks. In the rat studies, the major effects for both males and females included a 10% decrease in terminal body weight at 30 mg/kg/day, an increase in hematopoietic cell proliferation in the spleen at 10 and 30 mg/kg/day, and a responsive anemia at 10 and 30 mg/kg/day. A 15 to 30% decrease in platelet counts and a 20 to 40% decrease in thymus weights was observed at 10 and 30 mg/kg/day. An increase in liver weight up to 15% was found at 3 mg/kg/day and higher doses in males and at 10 and 30 mg/kg/day in females, respectively. An increase in spleen weights up to 15% was observed at 10 and 30 mg/kg/day in males and at 30 mg/kg/day in females. A marked decrease in circulating total thyroxine (TT4) was found in both males and females at all dose levels tested. TT4 could hardly be detected at 10 and 30 mg TCAB/kg/day. In addition, hyperplasia of the forestomach was increased at 3 mg/kg/day and higher doses in males and at 30 mg/kg/day in females. In the mouse studies, an increase in liver and spleen weight was observed up to approximately 25% in both males and females at 10 and 30 mg/kg/day. Hyperplasia of the forestomach was observed at 1 mg/kg/day and higher doses in both males and females. In males, a 30% decrease in thymus weights at 30 mg/kg/day and a 60% decrease in epididymal sperm density at 3 and 30 mg/kg/day was observed. Also in males, centrilobular hypertrophy of hepatocytes and an increase in hematopoietic cell proliferation in the spleen was observed at 3 mg/kg/day and higher doses. Based on the current study and information in the literature, TCAB has dioxin-like properties. Comparison of the effects of TCAB in the present study and in the literature to those with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) indicates that TCAB is from two to six orders of magnitude less potent than TCDD depending on the end point.
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PMID:Toxicity of 3,3',4,4'-tetrachloroazobenzene in rats and mice. 1019 80

3,3',4,4'-Tetrachloroazoxybenzene is not commercially manufactured but is present as a contaminant of 3,4-dichloroaniline and its herbicidal derivative Diuron(R). In addition, environmental contamination occurs when 3,3',4,4'-tetrachloroazoxybenzene is formed by the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazoxybenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazoxybenzene. The toxicity of 3,3',4,4'-tetrachloroazoxybenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), hepatic cell proliferation (rats only), cytochrome P(450)1A immunohistological staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Additional genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight, 5 days a week. Groups of five male and five female mice received 0, 1, 3.2, 10, 32, or 100 mg/kg in corn oil by gavage, 5 days a week. Major effects in rats included increases in liver and lung weights, and decreases in mean body weights and body weight gains, heart weights, and thymus weights. Effects in mice included increases in liver weights and decreases in thymus weights. No effects on survival were observed. Treatment-related lesions included cytoplasmic alteration of hepatocytes, splenic hematopoietic cell proliferation, thymic atrophy, and nephropathy in rats and thymic atrophy, splenic hematopoietic cell proliferation, and hepatic foci of inflammation and necrosis in mice. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'- tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg, 5 days a week. In the 13-week rat study, all males and seven females in the 30 mg/kg groups died. Decreases in final mean body weights and body weight gains were observed in 3 and 10 mg/kg males and 10 and 30 mg/kg females. Decreased thymus weights, accompanied by thymic atrophy observed microscopically, were observed at doses of 1 mg/kg or greater in males and females. Increased liver weights were observed in males and females administered 1 mg/kg or greater, and hepatic cytochrome P(450)1A staining was increased in 1 and 3 mg/kg males and 3, 10, and 30 mg/kg females. In addition, a responsive anemia and decreases in platelet counts were observed in dosed male and female rats. A marked decrease in circulating thyroxine concentrations was observed in dosed males and females. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. A decrease in epididymal spermatozoal motility was observed in all dosed groups tested. In 10 mg/kg females, the estrous cycle length was increased. Major effects included increased incidences of hyperplasia of the forestomach in 3, 10, and 30 mg/kg males and 10 and 30 mg/kg females. Increased incidences of centrilobular degeneration and hematopoietic cell proliferation were observed in the liver of dosed males and females. Furthermore, chronic active inflammation of the lung vasculature and hematopoietic cell proliferation in the spleen were observed in dosed males and females. The increased severities of cardiomyopathy and nephropathy in males and the incidences of cardiomyopathy and nephropathy and severity of cardiomyopathy in females were 3,3',4,4'-tetrachloroazoxybenzene related. In the 13-week mouse study, the major effects included increases in liver weights in males administered 3 mg/kg or greater and females administered 1 mg/kg or greater. Hyperplasia of the forestomach and dilatation of hair follicles were observed in 10 and 30 mg/kg males and 30 mg/kg females. Furthermore, thymus weights were decreased in males administered 3 mg/kg or greater and in 10 and 30 mg/kg females. Increased incidences of centrilobular hypertrophy of hepatocytes were observed in 10 and 30 mg/kg males and females. Increased incidences of hematopoietic cell proliferation in the spleen were observed in 30 mg/kg males and in 10 and 30 mg/kg females. Increases in the incidences of thymocyte necrosis were observed in 10 mg/kg males and in 10 and 30 mg/kg females. The incidences of splenic pigmentation were increased in all dosed groups of males, and the severity of pigmentation increased with increasing dose in males and females. 3,3',4,4'-Tetrachloroazoxybenzene was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535 with or without induced S9 metabolic activation enzymes. It did not induce significant increases in micronucleated erythrocytes in a three-exposure male mouse bone marrow micronucleus test up to dose levels of 200 mg/kg, but results of a 13-week peripheral blood micronucleus test conducted in male and female mice were positive. In summary, 3,3',4,4'-tetrachloroazoxybenzene caused typical dioxin-like effects, including thymic atrophy, increased liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, a marked decrease in circulating thyroxine concentrations was observed in male and female rats, even at the lowest dose (0.1 mg/kg) in female rats. A decrease in epididymal sperm motility was observed at all doses in rats. Effects on the hematopoietic system occurred at doses including and lower than those that caused histopathologic alterations in the liver. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. In male and female mice, the NOAEL was 1 and 0.1 mg/kg, respectively. Furthermore, treatment-related effects included increased incidences of hyperplasia of the forestomach epithelium in rats and mice, chronic active inflammation of the vasculature of the lung in rats, increased incidences and/or severities of cardiomyopathy and nephropathy in rats, and dilatation of the hair follicles in mice. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'- tetrachloroazoxybenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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PMID:NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazoxybenzene (CAS No. 21232-47-3) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1198 83

Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and mice of each sex; this lesion was more severe in rats than in mice. Inflammation of the liver, periportal to midzonal in distribution, occurred in rats in the 8000 and 16,000 ppm groups. Depletion of hematopoietic cells was evident in rats of each sex in the bone marrow (8000 and 16,000 ppm) and spleen (16,000 ppm). Kidneys of male and female rats in the 4000, 8000, and 16,000 ppm groups had an increased number and size of protein droplets in the epithelia of the renal cortical tubules. In the 13-week feed studies, groups of 10 rats per sex received diets containing 500 to 8000 ppm cupric sulfate, and groups of 10 mice per sex received diets containing 1000 to 16,000 ppm cupric sulfate for 92 days; estimates of cupric sulfate consumption ranged from 32 to 551 mg/kg per day for rats and 173 to 4157 mg/kg per day for mice. There were no chemical-related deaths in rats or mice, and no clinical signs of cupric sulfate toxicity were recorded. Final mean body weights were lower than those of the controls for animals of both species receiving doses of 4000 ppm cupric sulfate and greater. In mice in the 13-week studies, there was a dose-related decrease in liver weights. Hematologic, clinical chemistry, and urinalysis evaluations of rats in the 13-week study revealed variable chemical-related changes that were, for the most part, restricted to the 4000 and 8000 ppm groups. Increases in serum alanine aminotransferase and sorbitol dehydrogenase activities in both sexes were indicative of hepatocellular damage, as were increases in 5'-nucleotidase and bile salts in males. Decreases in mean cell volume, hematocrit, and hemoglobin indicated the development of a microcytic anemia, while increases in reticulocyte numbers at the same time points suggested a compensatory response to the anemia by the bone marrow. Increases in urinary glucose and N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme) and aspartate aminotransferase (alpha-cytosolic enzyme) were suggestive of renal tubule epithelial damage. Dose-related increases in copper occurred in all male rat tissues examined (lissues examined (liver, kidney, plasma, and testis). These increases were accompanied by increases in zinc in the liver and kidney. Plasma calcium was significantly reduced in the 4000 and 8000 ppm groups, and there was a trend toward reductions in calcium in the kidney and testis as well. In the 8000 ppm group, plasma magnesium was significantly increased relative to the controls. Rats in the three highest dose groups had hyperplasia and hyperkeratosis of the forestomach, inflammation of the liver, and increases in the number and size of protein droplets in the epithelial cytoplasm and the lumina of the proximal convoluted tubules. These effects were similar to those seen in the 2-week feed study, and the incidence and severity of these lesions were dose related. Many of the droplets in male rat kidneys were large and had irregular crystalline shapes. These droplets stained strongly positive for protein but were negative by iron, PAS, and acid-fast (lipofuscin) staining methods. α-2-Microglobulin was present in the droplets of male rats, but there was no dose- related, qualitative difference in the content of this protein. In the 4000 and 8000 ppm groups, copper was distributed in a periportal to midzonal pattern in the liver and was restricted to the cytoplasm of the proximal convoluted tubule epithelium in the kidney. Copper was present in some, but not all, of the protein droplets. Transmission electron microscopy of the livers of rats of each sex revealed increases in the number of secondary lysosomes in hepatocytes in the periportal area. In mice of each sex receiving 4000 ppm cupric sulfate and higher in the 13-week study, there was a dose-related increase in hyperplasia with hyperkeratosis of the squamous mucosa on the limiting ridge of the forestomach. Minimal positive staining for copper was present in the liver and was limited to high-dose (16,000 ppm) male and female mice. Cupric sulfate produced no adverse effects on any of the reproductive parameters measured in rats or mice of either sex. In summary, administration of cupric sulfate to rats in feed or drinking water resulted in significant gastric changes and hepatic and renal damage. The primary lesion in rats was an increase in the size and number of proteinaceous droplets in the epithelial cytoplasm and lumen of the proximal convoluted tubule. For rats in the 13-week study, the no-observed-adverse-effect level (NOAEL) for evidence of histologic injury to the kidney was 1000 ppm for males and 500 ppm for females, while the NOAEL for liver inflammation was 1000 ppm for males and 2000 ppm for females. Hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach was also seen in rats of each sex, and the NOAEL for this change was 1000-ppm cupric sulfate in the feed. Additionally, clinical pathology alterations noted in the 13-week study, along with histologic changes in bone marrow noted in the 2-week feed study, were indicative of a microcytic anemia with a compensatory bone marrow response. Mice appeared to be much more resistant to the toxic effects of cupric sulfate than rats. The primary target tissue in mice was the epithelium of the limiting ridge of the forestomach. The NOAEL for the hyperplasia and hyperkeratosis seen at this site in mice was 2000-ppm cupric sulfate in the feed. Synonyms: Chalcanthite; Copper sulfate; cupric sulfate pentahydrate; bluestone; blue vitriol; Roman vitriol; Salzburg vitriol. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)
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PMID:NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice. 1220 95

3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS) and persons seropositive for human immunodeficiency virus (HIV). The National Cancer Institute nominated AZT for toxicity and carcinogenicity studies because of the impending large-scale use of AZT in the treatment of adult patients with AIDS or AIDS-related complex. alpha-Interferon A/D, which displays antiviral activity in mice, is a hybrid molecule composed of the N-terminal portion of human alpha-interferon A and the C-terminal portion of human alpha-interferon D. AZT and alpha-interferon A/D combination studies were conducted because in vitro studies of AZT and alpha-interferon have demonstrated that the combination is more effective in blocking HIV infection than either agent alone. Male and female B6C3F1 mice received AZT (approximately 98% pure) in 0.5% aqueous methylcellulose by gavage for 14 weeks or 2 years. In addition, male and female B6C3F1 mice received alpha-interferon A or alpha-interferon A/D by subcutaneous injection for 2 years, and male and female B6C3F1 mice received AZT in 0.5%% aqueous methylcellulose by gavage in combination with alpha-interferon A/D by subcutaneous injection for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow erythrocytes, and mouse peripheral blood erythrocytes. 14-WEEK AZT STUDY: Groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 50, 100, 200, 800, or 2,000 mg/kg daily for 14 weeks. Additional groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 100, 800, or 2,000 mg/kg daily for 14 weeks and then were held without treatment for an additional 4 weeks before necropsy. One female receiving 100 mg/kg and two females receiving 200 mg/kg died during week 1 as a result of gavage trauma; one female receiving 2,000 mg/kg also died prior to the end of the 14-week dosing period. One female receiving 2,000 mg/kg in the recovery study also died from gavage trauma during week 1. The final mean body weights of dosed mice were similar to those of the vehicle control groups at the end of the dosing period and at the end of the recovery period. Female mice receiving 200, 800, or 2,000 mg/kg gained less weight than the vehicle controls during the 14-week dosing period. Exposure to AZT was toxic to the bone marrow, resulting in significant changes in the peripheral blood (decreased hematocrit values, erythrocyte counts, and hemoglobin concentrations, and increased mean cell volume and mean cell hemoglobin) and bone marrow (erythroid hypoplasia) characteristic of a dose- and time-dependent, minimal to moderate, poorly regenerative macrocytic anemia. At the end of the 4-week recovery period, the hematology parameters had returned to normal, indicating that the hematotoxicity was reversible. 2-YEAR STUDIES: AZT Groups of 95 male and 95 female mice received AZT in 0.5% methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, administered as two equal doses at least 6 hours apart, 5 days per week for 105 weeks. Each group of 95 animals was composed of a core group of 50 animals for evaluation of carcinogenic response, a group of 30 animals for evaluation of hematology and bone marrow cellularity, and a group of 15 animals from which blood was drawn for determination of plasma AZT concentrations at week 54. alpha-Interferon A/D and AZT/alpha-Interferon A/D Studies Groups of 80 male and 80 female mice received AZT in 0.5% aqueous methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, given in two equal doses, 5 days per week for 105 weeks. Those groups receiving AZT also received sub-cutaneous injections of 500 or 5,000 U alpha-interferon A/D three times per week for 105 weeks. Additional groups of 80 male and 80 female mice received subcutaneous injections of the vehicle, 500 U alpha-interferon A/D, 5,000 Uutaneous injections of the vehicle, 500 U α-interferon A/D, 5,000 U α-interferon A/D, or 5,000 U α-interferon A, three times per week for 105 weeks. Each group of 80 animals was composed of a core group of 50 animals for evaluation of carcinogenic response and a group of 30 animals for evaluation of hematology and bone marrow cellularity. Because of the large number of animals involved, the 2-year studies were started in four phases and, for clarity, are presented as follows: the AZT study, the α-interferon A/D study, the AZT/500 U α-interferon A/D study, and the AZT/5,000 U α-interferon A/D study. Design of the 2-year AZT, AZT/α-Interferon A/D, and α-Interferon A/D Studies AZT Dose AZT Study AZT/500 U α-Interferon A/D Study AZT/5,000 U α-Interferon A/D Study 500 or 5,000 U α-Interferon A/D or 5,000 U α-Interferon A Study Vehicle Control 95 male and 95 female micea 80 male and 80 female miceb 80 male and 80 female miceb 80 male and 80 female miceb 30 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 60 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 120 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none aFor the AZT study, there were 95 male and 95 female mice; these were divided into 50 males and 50 females in the core groups, 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only), and 15 males and 15 females for plasma AZT concentration determinations. bFor the α-interferon A/D study and the AZT/α-interferon A/D studies, there were 80 male and 80 female mice for each study; these were divided into 50 males and 50 females in the core groups and 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only). Survival and Body Weights Survival and mean body weights of mice exposed to AZT, α-interferon A, α-interferon A/D, or AZT plus α-interferon A/D were generally similar to those of the vehicle control groups. Hematology and Bone Marrow Analyses All groups of male and female mice receiving AZT exhibited changes in peripheral blood and bone marrow characteristic of a dose- and time-dependent, minimal to mild, macrocytic, nonresponsive anemia. In females, these changes were evident throughout the study. In males, the macrocytic anemia had resolved by week 80 in the 30 mg/kg group; at study termination erythrocyte macrocytosis was present only in males receiving 60 or 120 mg/kg AZT or AZT plus α-interferon A/D. There were no treatment-related alterations in hematology or bone marrow parameters in groups that received only α-interferon A or A/D. Pathology Findings Incidences of squamous cell carcinoma and squamous cell papilloma or carcinoma (combined) of the vagina occurred with a positive trend and were significantly increased in groups of female mice receiving 60 or 120 mg/kg AZT alone or in combination with α-interferon A/D. Epithelial hyperplasia was observed in all dosed groups of females, and the incidence was significantly increased in the 120 mg/kg AZT group. Three renal tubule adenomas and one renal tubule carcinoma were observed in male mice receiving 120 mg/kg AZT; the combined incidence in this group exceeded the range in historical controls. A renal tubule adenoma was observed in one male receiving 60 mg AZT/kg and 500 U α-interferon A/D; how ever, none were observed in other groups. Evaluation of step sections revealed a few more renal tubule hyperplasias but no additional neoplasms. The incidence of harderian gland adenoma was increased in male mice receiving 120 mg/kg AZT and exceeded the range in historical controls. Harderian gland neoplasms were observed in other groups but did not follow a treatment-related pattern. Overall Incidences of Vaginal Neoplasms and Hyperplasia of the Vaginal Epithelium in Female Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 2/197 (1&percnt;)b 1/197 0/49 (0&percnt;) 3/49 5/45 (11%&percnt;) 4/45 11/49 (22%&percnt;) 11/49 500 U α-Interferon A/D 0/49 (0%&percnt;) 0/49 0/44 (0&percnt;) 4/44 5/48 (10&percnt;) 8/48 6/48 (13&percnt;) 12/48 5,000 U α-Interferon A/D 1/50 (2&percnt;) 1/50 1/48 (2&percnt;) 4/48 5/48 (10&percnt;) 8/48 4/50 (8&percnt;) 15/50 aData are presented as number of vaginal neoplasms/number of animals microscopically examined (first line) and number of vaginal hyperplasias/number of animals microscopically examined (second line) bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidences in the vehicle control group from the AZT alone study are 0/50 (0%&percnt;) (neoplasms) and 0/50 (hyperplasia) Overall Incidence of Harderian Gland Neoplasms in Male Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 13/200 (6%&percnt;)b 5/50 (10%&percnt;) 2/50 (4&percnt;) 10/50 (20%&percnt;) 500 U α-Interferon A/D 3/50 (6&percnt;) 3/50 (6&percnt;) 1/50 (2%&percnt;) 4/50 (8%&percnt;) 5,000 U α-Interferon A/D 3/50 (6&percnt;) 9/50 (18%&percnt;) 4/50 (8%&percnt;) 4/50 (8&percnt;) aData are presented as number of harderian gland neoplasms/number of animals necropsied bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidence in the vehicle control group from the AZT alone study is 3/50 (6&percnt;) Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver consistent with an infection with Helicobacter hepaticus. An organism compatible with H. hepaticus was confirmed by polymerase chain reaction-restriction fragment length polymorphism-based assays. Detection of dose-related differences in neoplasm incidences in these studies was not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: AZT is mutagenic in vitro and in vivo. It induced gene mutations in Salmonella typhimurium strain TA102, with and without S9; no increases in mutations were noted in the other tested strains of S. typhimurium. AZT induced sister chromatid exchanges, but not chromosomal aberrations, in cultured Chinese hamster ovary cells, with and without S9. In vivo studies with male mice administered AZT by gavage showed highly significant increases in micronucleated erythrocytes in bone marrow and peripheral blood after exposure periods that ranged from 72 hours to 14 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on increased incidences of renal tubule and harderian gland neoplasms in groups receiving AZT alone. There was clear evidence of carcinogenic activity of AZT in female mice based on increased incidences of squamous cell neoplasms of the vagina in groups that received AZT alone or in combination with α-interferon A/D. Hematotoxicity occurred in all groups that received AZT. Treatment with AZT alone and AZT in combination with α-interferon A/D resulted in increased incidences of epithelial hyperplasia of the vagina in all dosed groups of females. Synonyms: AZT; 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine Trade name: Retrovir®
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PMID:NTP Toxicology and Carcinogenesis Studies of AZT (CAS No. 30516-87-1) and AZT/alpha-Interferon A/D B6C3F1 Mice (Gavage Studies). 1257 4

Isobutyl nitrite is used to a limited extent as an intermediate in the syntheses of aliphatic nitrites. It is also an ingredient of various incenses or room odorizers and is used as a euphoric. The chemical has also been used as a jet propellant and in the preparation of fuels. Isobutyl nitrite was nominated by the Consumer Product Safety Commission to the NTP for toxicology and carcinogenicity studies because of its possible contribution to the high incidence of Kaposi's sarcoma among male homosexual acquired immune deficiency syndrome patients and because of the lack of available data on the potential carcinogenicity of isobutyl nitrite. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyl nitrite (purity of 93% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All males and females exposed to 600 or 800 ppm and one 400 ppm female died on the first day of the study. Final mean body weights and mean body weight gains of 400 ppm males and females were significantly lower than those of the controls. Clinical findings observed in 400 ppm males and females included ocular discharge, lethargy, hunched posture, and rough coats. Absolute and relative lung weights of all exposed groups of males and of 200 and 400 ppm females were less than those of the controls. Chemical-related hyperplasia of the bronchial epithelium was observed in 200 and 400 ppm males and females and hyperplasia of the nasal turbinate epithelium was observed in rats exposed to 400 ppm or less. Hemosiderin pigmentation was observed in the spleen of 200 and 400 ppm males and females and bone marrow hematopoietic hyperplasia was observed in rats exposed to 400 ppm or less. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 100, 200, 400, 600, or 800 ppm (approximately 420, 840, 1,700, 2,500, or 3,300 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. Three males and four females exposed to 800 ppm died before the end of the study. Final mean body weights and mean body weight gains of 600 and 800 ppm males and females were significantly lower than those of the controls. Mice exposed to 400 ppm or greater were lethargic and exhibited hunched posture and rough coats. Absolute and relative lung weights of 600 and 800 ppm males and the relative lung weight of 600 ppm females were significantly greater than those of the controls. Chemical-related hyperplasia of the bronchiolar epithelium was observed in all exposed groups of males and females. Lymphocytic atrophy of the spleen and thymus was observed in males and females exposed to 400 ppm or greater. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. All rats survived to the end of the study. Final mean body weights and mean body weight gains of 300 ppm males and females were significantly lower than those of the controls, as was the mean body weight gain of 150 ppm females. Clinical findings observed during the study included ruffled fur in 300 ppm males and females, hypoactivity in 300 ppm males, and hyperactivity in 150 and 300 ppm females. A very mild chemical-related methemoglobinemia and anemia occurred in male and female rats in the 75, 150, and 300 ppm groups. Hematopoietic hyperplasia occurred in the bone marrow of all exposed groups of males and females and was considered to be a secondary response to the anemia and methed methemoglobinemia. There was minimal hemosiderin pigment accumulation in the spleens of males and females exposed to 75 ppm or greater, mild to moderate epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males and females, and minimal hyperplasia occurred in 150 ppm males and females. Hyperplasia of the bronchial epithelium was observed in 300 ppm males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 10, 25, 75, 150, or 300 ppm (approximately 42, 105, 315, 630, or 1,260 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week for 13 weeks. There were no chemical-related deaths. Final mean body weights and mean body weight gains of 150 and 300 ppm females were significantly less than those of the controls. Final mean body weights and mean body weight gains of exposed groups of males were similar to those of the controls. There were no chemical-related clinical findings. A very mild chemical-related methemoglobinemia occurred in male and female mice in the 150 and 300 ppm groups. A very mild anemia occurred in the 300 ppm groups. In the lung, increased incidences of mild to moderate hyperplasia of the bronchiolar epithelium occurred in males and females exposed to 300 ppm. Minimal hyperplasia occurred in males exposed to 75 ppm or greater and in females exposed to 150 ppm. Minimal epithelial cell hyperplasia of the nasal mucosa was observed in 300 ppm males. Increased hematopoiesis of the spleen, secondary to the hematotoxicity, occurred in males exposed to 75 ppm or greater and in females exposed to 150 or 300 ppm. Increased hemosiderosis of the spleen occurred in males exposed to 300 ppm and in females exposed to 75 ppm or greater. 2-YEAR STUDY IN RATS: Based on the low final mean body weights, anemia, and the mild to moderate nasal mucosal lesions and the hyperplastic bronchial lesions observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in rats were 37.5, 75, and 150 ppm. Groups of 56 male and 56 female rats were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. Ten male and 10 female rats from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, Hematology, and Clinical Chemistry: Survival rates of exposed groups of rats were greater than those of the controls, and the survival rates of 75 and 150 ppm males were significantly greater than that of the control. Mean body weights of 150 ppm males and females were 3&percnt; to 11&percnt; lower than those of the controls throughout the course of the study. There were no clinical findings considered to be related to isobutyl nitrite exposure. A very mild methemoglobinemia and anemia occurred in male and female rats exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms in 75 ppm males and in 150 ppm males and females were significantly greater than those in the controls. The incidence of alveolar/bronchiolar carcinoma was significantly greater in 150 ppm male rats than that in the controls. The incidences of alveolar epithelial hyperplasia were also increased in 75 and 150 ppm males and in all exposed groups of females. The incidences of mononuclear cell leukemia in exposed groups of males and females were significantly less than those in the controls. 2-YEAR STUDY IN MICE: Based on the low final mean body weight of 300 ppm females and the mild to moderate bronchiolar hyperplasia observed in 300 ppm males and females, isobutyl nitrite exposure concentrations selected for the 2-year inhalation study in mice were 37.5, 75, and 150 ppm. Groups of 60 male and 60 female mice were exposed to 0, 37.5, 75, or 150 ppm (equivalent to 0, 158, 315, or 630 mg/m(3)) isobutyl nitrite by inhalation for 6 hours per day, 5 days per week, for 103 weeks. As many as 10 male and 10 female mice from each group were evaluated at 15 months for clinical pathology and histopathology. Survival, Body Weights, Clinical Findings, and Hematology and Clinical Chemistry: Survival rates of exposed groups of males were similar to those of the controls. Survival rates of exposed groups of females were greater than those of the controls, and the survival rate in 37.5 ppm females was significantly greater than that of the controls. Mean body weights of exposed groups of males and of 37.5 and 75 ppm females were similar to those of the controls throughout the study. Mean body weights of 150 ppm females were lower than those of the controls from week 20 until the end of the study. There were no biologically significant clinical findings noted in the 2-year study in mice. A very mild methemoglobinemia and anemia occurred in male and female mice exposed to 75 or 150 ppm. Pathology Findings: Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) occurred with significant positive trends in exposed males and females, and the incidences of these neoplasms were significantly greater than those in the controls in 75 ppm males and in 150 ppm males and females. Incidences of alveolar epithelial hyperplasia were significantly increased in 75 and 150 ppm male and female mice. Thyroid gland follicular cell adenoma occurred with a significant positive trend in male mice; the incidences of thyroid gland follicular cell hyperplasia were increased in all exposed groups of males, and the incidences in males exposed to 37.5 or 150 ppm were significantly greater than those in the controls. Incidences of serous exudate and olfactory epithelium atrophy in the nose of 150 ppm females were significantly greater than those in the controls. Incidences of minimal to mild hemosiderin pigment in the spleen of 75 and 150 ppm male mice were significantly greater than those in the controls. GENETIC TOXICOLOGY: Isobutyl nitrite was found to be mutagenic in vitro and in vivo. It induced base-pair substitution mutations in Salmonella typhimurim strains TA100 and TA1535 and sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Positive responses in the S. typhimurium tests required S9 activation, but isobutyl nitrite induced chromosomal effects in cultured Chinese hamster ovary cells with and without S9. In vivo, no induction of sex-linked recessive lethal mutations was noted in the germ cells of male Drosophila melanogaster exposed to isobutyl nitrite via feeding or injection. However, significant increases in micronucleated normochromatic erythrocytes were observed in the peripheral blood of male and female mice treated with isobutyl nitrite for 90 days by inhalation. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of isobutyl nitrite in male and female F344/N rats based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of isobutyl nitrite in male and female B6C3F1 mice based on the increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females. The increased incidence of thyroid gland follicular cell adenoma in male mice may have been related to isobutyl nitrite exposure. Exposure of rats and mice to isobutyl nitrite by inhalation for 2 years resulted in increased incidences of alveolar epithelial hyperplasia (male and female rats and mice), thyroid gland follicular cell hyperplasia and splenic hemosiderin pigmentation (male mice), and serous exudate and atrophy of the olfactory epithelium of the nose (female mice). Exposure of rats to isobutyl nitrite by inhalation for 2 years resulted in decreased incidences of mononuclear cell leukemia in males and females.
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PMID:NTP Toxicology and Carcinogenesis Studies of Isobutyl Nitrite (CAS No. 542-56-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1259 27

o-Nitroanisole is used as an intermediate for the preparation of o-anisidine and in the manufacture of azo dyes. Toxicology and carcinogenesis studies were conducted by administering o-nitroanisole (>99% pure) in the diet to groups of male and female F344 rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and mouse lymphoma cells. 14-DAY STUDIES: Groups of five male and five female F344 rats received diets containing 0, 583, 1,166, 2,332, 4,665, or 9,330 ppm o-nitroanisole. Mean body weight gains and final mean body weights of males in the 4,665 and 9,330 ppm groups were lower than those of the controls. Absolute liver weights were significantly increased in males receiving 1,166 ppm or more and in females receiving 583 ppm or more. Groups of five male and five female B6C3F1 mice received diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm o-nitroanisole. Mean body weight gains and final mean body weights of males that received 250 ppm and females that received 4,000 ppm were significantly lower than those of the controls. No other chemical-associated effects were observed. 13-WEEK STUDIES: Groups of 10 male and 10 female F344 rats received diets containing 0, 200, 600, 2,000, 6,000, or 18,000 ppm o-nitroanisole. Final mean body weights and feed consumption by male and female rats receiving 6,000 and 18,000 ppm were lower than those of the controls. Hemoglobin and hematocrit values were significantly lower and methemoglobin levels significantly higher in males in the 6,000 and 18,000 ppm groups than in controls. Absolute liver weights were significantly increased in females that received 200, 600, 2,000, and 6,000 ppm, absolute kidney weights were significantly increased in males that received 600, 2,000, and 6,000 ppm, and absolute spleen weights were significantly increased in males and females that received 6,000 and 18,000 ppm. Groups of 10 male and 10 female B6C3F1 mice received diets containing 0, 60, 200, 600, 2,000, or 6,000 ppm o-nitroanisole. Final mean body weight gains, final mean body weights, and feed consumption by male and female mice receiving 6,000 ppm were lower than those of the controls. Hemoglobin and hematocrit values in males and females that received 2,000 or 6,000 ppm were significantly lower than those in the controls. The absolute and relative liver weights of females in the 600 ppm group and relative liver weights of males and females in the 2,000 and 6,000 ppm groups were significantly greater than those of controls. Lesions associated with exposure to o-nitroanisole were present in the urinary bladder, spleen, kidney, liver, testis, and uterus of rats. Diffuse hyperplasia of the transitional epithelium of the urinary bladder occurred in all male and female rats that received 6,000 and 18,000 ppm. A transitional cell papilloma occurred in one male and transitional cell carcinomas occurred in two males and three females receiving 18,000 ppm. Congestion of the red pulp and capsular hyperplasia of the spleen and hepatocellular hypertrophy of the liver were present in males and females from the 18,000 ppm groups. Multifocal degeneration and necrosis of the renal tubule epithelium with infiltration of mononuclear inflammatory cells were present in male rats that received 600, 2,000, and 6,000 ppm. At the 18,000 ppm level, degeneration of the seminiferous epithelium accompanied by loss of spermatogenic cells and decreased numbers of spermatozoa were observed in the testes of male rats, while uterine atrophy was observed in female rats. Hepatocyte hypertrophy of the centrilobular and midzonal regions of liver lobules was present in mice that received 200 ppm and increased in severity at higher exposure levels. 2-YEAR STUDIES: The doses selected for the 2-year study of o-nitroanisole in rats were based on lower mean body weights, reduced feed consumption, and increased severity of regenerative anemia in male and female rats receiving 6,000 and 18,000 ppm during the 13-week study. Groups of 6roups of 60 male and 60 female F344 rats received diets containing 0, 222, 666, or 2,000 ppm o-nitroanisole. Groups of 60 male and 60 female B6C3F1 mice received diets containing 0, 666, 2,000, or 6,000 ppm o-nitroanisole. After 15 months, up to 10 animals from each group were evaluated for chemical-related lesions. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of male rats receiving 2,000 ppm was significantly lower than that of the controls due to increased severity of nephropathy. Survival of 222 and 666 ppm male rats and all exposed female rats was similar to that of the controls. Survival of groups of exposed male and female mice was similar to that of the controls. The final mean body weight of male rats receiving 2,000 ppm was lower than that of the controls. Final mean body weights of male and female mice that received 2,000 and 6,000 ppm were lower than those of the controls. Feed consumption by male and female rats was similar to that by the controls. The only clinical finding in male or female mice attributable to chemical administration was discolored urine. Neoplasms and Nonneoplastic Lesions: The incidence of mononuclear cell leukemia was significantly increased in male rats that received 666 and 2,000 ppm and in female rats that received 2,000 ppm (males: 0 ppm, 26/50; 222 ppm, 25/50; 666 ppm, 42/50; 2,000 ppm, 34/50; females: 14/50, 11/50, 14/50, 26/50). Nephropathy occurred in all male rats; the severity increased with exposure level. Focal hyperplasia of the renal tubule epithelium was present in three males receiving 222 ppm and two males receiving 2,000 ppm. Renal tubule adenomas occurred in one male from each of the 222, 666, and 2,000 ppm groups, and renal tubule carcinomas occurred in two males from the 2,000 ppm group. Focal hyperplasia of the transitional epithelium of the urinary bladder was present in one female rat that received 222 ppm and two male rats and six female rats that received 2,000 ppm. A transitional cell papilloma occurred in the urinary bladder of one female rat from the 2,000 ppm group, and a transitional cell carcinoma occurred in another female from the 2,000 ppm group. The incidence of forestomach ulcers increased in male rats that received 2,000 ppm, and the incidence of focal hyperplasia of the forestomach increased with exposure level in male and female rats. In addition, squamous cell papillomas of the forestomach were present in one female receiving 222 ppm, one male receiving 666 ppm, and one male and one female receiving 2,000 ppm, while squamous cell carcinomas were present in one male receiving 666 ppm and one male and one female receiving 2,000 ppm. The incidences of pituitary gland adenomas in male rats and mammary gland fibroadenomas in female rats decreased with exposure level. The incidence of cellular alteration in the liver was significantly increased in exposed groups of male and female mice. The incidences of hepatocellular adenoma, hepatocellular adenoma or carcinoma (combined), and hepatocellular carcinoma or hepatoblastoma (combined) were significantly increased in male mice receiving 2,000 and 6,000 ppm. The incidences of hepatocellular adenoma or carcinoma were significantly increased in female mice that received 2,000 ppm. STOP-EXPOSURE STUDY: Groups of 60 male and 60 female F344 rats received diets containing 0, 6,000, or 18,000 ppm o-nitroanisole for 27 weeks and were then maintained on control feed without further chemical exposure for up to an additional 77 weeks. Up to 10 rats from each group were evaluated for the presence of chemical-related lesions at 3, 6, 9, and 15 months. Survival and Body Weights: Survival of exposed male and female rats was significantly lower than that of the controls as a result of moribund deaths associated with significantly increased incidences of urinary bladder neoplasms, primarily transitional cell carcinomas. All male rats that received 18,000 ppm were dead by week 48 and all females that received 18,000 ppm were dead by week 61. Mean body weights of exposed male and female rats were lower than those of the controls throughout the study. Neoplasms and Nonneoplastic Lesions: Hyperplasia of the transitional epithelium of the urinary bladder was present in nearly all exposed male and female rats examined at the interim evaluations. A transitional cell carcinoma was first observed at the 3-month interim evaluation in a male rat that received 18,000 ppm. At the 6- and 9-month interim evaluations, transitional cell papillomas or carcinomas were observed in both exposed groups of male rats. Transitional cell carcinomas were observed at the 6-month interim evaluation in females receiving 18,000 ppm and at the 9-month interim evaluation in females receiving 6,000 and 18,000 ppm. Adenomatous polyps of the large intestine were observed in a small number of exposed rats at the 6-, 9-, and 15-month interim evaluations. At the end of the study, the incidence of adenomatous polyps of the large intestine was significantly increased in all exposed groups and carcinomas of the large intestine were present in four males and two females from the 18,000 ppm groups. The incidence of hyperplasia of the transitional epithelium of the kidney pelvis was significantly increased in exposed male and female rats and transitional cell papillomas were present in three males and one female that received 18,000 ppm. Transitional cell carcinomas of the kidney were present in one male receiving 6,000 ppm and six males and one female receiving 18,000 ppm. Transitional cell carcinomas of the urinary bladder were seen in nearly all exposed male and female rats. Of the males and females receiving 6,000 ppm which were without carcinomas, three males and one female had transitional cell papillomas. Generalized centrilobular hypertrophy, focal hepatocellular necrosis, multifocal hepatocellular cytoplasmic vacuolation, and Kupffer cell pigmentation were observed in the livers of male and female rats at the 3- and 6-month interim evaluations; however, only Kupffer cell pigmentation was observed at the end of the study. Congestion of the red pulp of the spleen was observed in nearly all exposed male and female rats at the 3-, 6-, and 9-month interim evaluations but the incidence was only slightly increased in the 18,000 ppm groups at the end of the study. Degeneration and atrophy of the seminiferous tubule epithelium of the testes were observed at the 3- and 6-month interim evaluations in all male rats receiving 18,000 ppm. GENETIC TOXICOLOGY: o-Nitroanisole was tested in two laboratories for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 with and without exogenous metabolic activation (S9). Positive responses were observed at both laboratories in TA100 with and without S9 activation. One laboratory found no increase in mutations, while the second laboratory detected a weakly positive response in TA1535 without S9. No mutagenic activity was observed in the other tester strains. o-Nitroanisole was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells without S9 activation. In cytogenetic tests with Chinese hamster ovary cells, o-nitroanisole induced a significant increase in chromosomal aberrations at the highest dose tested in the presence of S9 activation; sister chromatid exchanges were induced both with and without S9. CONCLUSIONS: Under the conditions of these feed studies there was clear evidence of carcinogenic activity of o-nitroanisole in male and female F344 rats that received diets containing 6,000 or 18,000 ppm for 6 months based on overall increased incidences of benign and malignant neoplasms of the urinary bladder, transitional cell neoplasms of the kidney, and benign and malignant neoplasms of the large intestine. There was a chemical-related increased incidence of mononuclear cell leukemia in male and female rats receiving diets containing 222, 666, or 2,000 ppm o-nitroanisole for 2 years. Marginally increased incidences of uncommon renal tubule neoplasms in male rats and forestomach neoplasms in male and female rats were considered uncertain findings. There was clear evidence of carcinogenic activity of o-nitroanisole in male B6C3F1 mice based on increased incidences of benign and malignant hepatocellular neoplasms. There was some evidence of carcinogenic activity of o-nitroanisole in female B6C3F1 mice based on increased incidences of hepatocellular adenomas. Increased severity of nephropathy in male rats, and increased incidences of focal hyperplasia of the renal tubule epithelium and forestomach ulcers in male rats, and of transitional cell hyperplasia of the urinary bladder, focal hyperplasia of the forestomach, and hyperplasia of transitional epithelium of the kidney pelvis in male and female rats were associated with exposure to o-nitroanisole. Synonyms: Methoxynitrobenzene, nitrophenyl methyl ether
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PMID:NTP Toxicology and Carcinogenesis Studies of o-Nitroanisole (CAS No. 91-23-6) in F344 Rats and B6C3F1 Mice (Feed Studies). 1261 95

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