UMLS:C0001430 - FACTA Search

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Query: UMLS:C0001430 (adenoma)
21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to evaluate the efficacy and role of technetium-99m tetrofosmin for the detection of abnormal parathyroid glands to be referred for surgical treatment. Twenty-eight consecutive patients, including 25 primary and 3 secondary cases of hyperparathyroidism, were evaluated. (99m)Tc-tetrofosmin/(99m)Tc-pertechnetate subtraction scintigraphy (TF/Tc) was performed on all patients, and the results were directly compared with those of (99m)Tc-methoxyisobutylisonitrile (MIBI)/(99m)Tc-pertechnetate subtraction scintigraphy (MIBI/Tc), (201)Tl/(99m)Tc-pertechnetate subtraction scintigraphy (Tl/Tc), magnetic resonance imaging (MRI) and ultrasonography (US). In cases of single-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 63.2%, 68.4%, 57.9%, 55.6% and 63.2%, respectively. In cases of multi-gland disease, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 41.7%, 41.7%, 37.5%, 58.3% and 54.2%, respectively. In cases of parathyroid adenoma, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 68.8%, 75.0%, 68.8%, 62.5% and 75.0%, respectively. In cases of parathyroid hyperplasia, the sensitivities of TF/Tc, MIBI/Tc, Tl/Tc, MRI and US were 40.7%, 40.7%, 33.3%, 53.8% and 48.1%, respectively. It is concluded that, for the detection of abnormal parathyroid glands, (99m)Tc-tetrofosmin is as useful as (99m)Tc-MIBI and is more useful than (201)Tl.
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PMID:Technetium-99m tetrofosmin for parathyroid scintigraphy: a direct comparison with (99m)Tc-MIBI, (201)Tl, MRI and US. 1173 21

A pancreas carcinoid, an adrenocortical adenoma, three parathyroid adenomas and a parathyroid hyperplasia of 5 MEN1 patients were used for loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies. The MEN1 gene is located in the region 11q13, approximately 30 kb distal to PGYM. Four tumors showed LOH on chromosome 11q13 (D11S11335, PGYM, D11S1883, FGF3, D11S937) however LOH was also found beyond 11q13. The pancreas carcinoid and adrenocortical adenoma, both from the same patient, showed LOH at marker 11q23.3 and 11q25. In the three parathyroid adenomas LOH was detected in five different markers: 11q21, 11q22.3, 11q23.2, 11q23.3 and 11q25. No LOH was found in parathyroid hyperplasia. CGH analysis showed in case of the pancreas carcinoid losses on chromosomes 1p, 2q, 3, 6, 9p, 11 and 12p. Gains were found at 4, 5, 7, 8, 13, 14, 15q, 18, 19. The parathyroid adenoma of the third patient showed losses only on chromosome 11 in the region 11p12-p15 and 11q12-q23. Our data indicate that other genes are involved in the tumorigenesis of the MEN1 syndrome. Especially the numerous allelic losses between markers 11q23 and 11q25 (D11S938 and D11S910) are a hint for further tumor suppressor genes on chromosome 11.
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PMID:Cytogenetic and molecular analyses of multiple endocrine neoplasias of the MEN1 syndrome. 1195 91

Deletion of chromosome 11q23 is a common alteration in parathyroid adenomas and hyperplasias. A new potential suppressor gene PPP2R1B encoding the beta isoform of the A subunit of the serine/threorine protein phosphatase 2A was recently identified and localized to chromosome 11q23. We performed polymerase chain reaction-based single-strand conformation polymorphism and direct sequencing on six parathyroid hyperplasias and 12 adenomas to evaluate the role of PPP2R1B in the pathogenesis of parathyroid lesions. A previously identified germline G-A transition (GGC-GAC) in codon 90, changing glycine (Gly) to aspartic acid (Asp), was detected in one adenoma. Both the common Gly allele and the variant Asp allele were detected by direct sequencing in the patient's somatic cells. We conclude mutations of PPP2R1B are not frequent in parathyroid lesions, and that other genes located at 11q23 may be more closely associated with pathogenesis of parathyroid hyperplasia and adenoma.
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PMID:Alterations in the suppressor gene PPP2R1B in parathyroid hyperplasias and adenomas. 1199 89

The morphologic distinction between parathyroid carcinoma and adenoma can be a difficult diagnostic problem. We analyzed nuclear immunoreactivity for the cell cycle-associated antigen Ki-67 with monoclonal antibody (MAb) MIB-1 and for retinoblastoma (RB) protein with two polyclonal antisera in 24 parathyroid carcinomas and 35 adenomas, which were formalin fixed and paraffin embedded to determine if these antibodies could assist in distinguishing between carcinomas and adenomas. In addition, 10 cases of parathyroid hyperplasia and 5 cases of normal parathyroids were examined as control tissues. The Ki-67 labeling index was significantly higher in parathyroid carcinomas compared to adenomas (7.1 +/- 1.0% vs 2.4 +/- 0.2%, p <0.001). No patient with a parathyroid adenoma, parathyroid hyperplasia, or normal parathyroid gland had a Ki-67 labeling index >5.3%. Analysis of the primary tumors from patients with recurrent carcinomas and from those with nonrecurrent carcinomas showed a higher mean Ki-67 labeling index (7.8 +/- 1.5% vs 5.2 +/- 1.1%) in the former group. Although these differences were not statistically significant, the RB protein immunoreactivity was not useful in distinguishing between parathyroid carcinomas and adenomas in paraffin-tissue sections. These results indicate that nuclear immunoreactivity for the cell cycle-associated antigen Ki-67 may be another useful method to assist in distinguishing parathyroid carcinomas from adenomas.
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PMID:Immunohistochemical Analysis of the Cell Cycle-Associated Antigens Ki-67 and Retinoblastoma Protein in Parathyroid Carcinomas and Adenomas. 1211 10

Technetium-99m sestamibi imaging for parathyroid adenoma localization has been performed using both dual-tracer subtraction and double-phase single-tracer washout techniques. The relative accuracy of these two techniques is uncertain. We have developed a modified imaging technique which combines both approaches and have directly compared them in a series of patients with surgically explored hyperparathyroidism. Initial injection of (99m)Tc-pertechnetate 50 MBq was followed by continuous dynamic imaging of the anterior neck for 30 min. (99m)Tc-sestamibi 1,000 MBq was injected intravenously at the midpoint of the acquisition. Delayed images were performed after 2 h. We blindly reviewed 88 consecutive cases of surgically explored hyperparathyroidism that had undergone preoperative scintigraphic localization with this procedure. Images were reformatted to display subtraction-only, early/delayed sestamibi-only and combined images. Scans were reviewed in random order. Of the 68 cases with solitary parathyroid adenoma, the sestamibi-only images gave correct localization in 49 (72%) while there was a statistically significant improvement in accuracy using the subtraction-only images (58 of 68, 85%, P=0.05) and the combined images (61 of 68, 90%, P=0.0015). Reader confidence was also greater with the subtraction-only and combined images than with the sestamibi-only images. Scan performance with parathyroid hyperplasia was less satisfactory. Although the largest gland was usually correctly identified, hyperplasia was difficult to distinguish from a solitary adenoma. Dual-tracer subtraction parathyroid imaging is superior to double-phase sestamibi-only imaging. The washout data may provide additional information in some cases, however, and an approach that combines both techniques may be optimal.
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PMID:Parathyroid 99mTc-sestamibi scintigraphy: dual-tracer subtraction is superior to double-phase washout. 1245 89

Furan serves as an intermediate in the synthesis and preparation of numerous linear polymers used to prepare temperature-resistant structural laminates and to prepare copolymers used in machine dishwashing products as alternatives to phosphorus- and nitrogen-containing detergents. Toxicology and carcinogenesis studies were conducted by administering furan (purity > 99%) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, mouse bone marrow cells, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. 16-Day Studies: Groups of five male rats received doses of 0, 5, 10, 20, 40, or 80 mg of furan per kg of body weight and groups of five female rats and five mice of each sex received doses of 0, 10, 20, 40, 80, and 160 mg/kg in corn oil by gavage. All male and female mice and female rats that received 160 mg/kg, all male and female rats and all male and four female mice that received 80 mg/kg, and three male mice that received 40 mg/kg died by day 8. Final mean body weights of male rats that received 20 mg/kg and of male and female rats that received 40 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 10 or 20 mg/kg were significantly greater than controls. Mottled and enlarged livers were observed at necropsy in male rats that received 20, 40, or 80 mg/kg and in females that received 40, 80, or 160 mg/kg. No lesions were observed at necropsy that were considered related to furan administration in mice. 13-Week Studies: Groups of 10 rats of each sex and groups of 10 female mice received doses of 0, 4, 8, 15, 30, or 60 mg of furan per kg of body weight, and groups of 10 male mice received doses of 0, 2, 4, 8, 15, or 30 mg/kg in corn oil by gavage. Nine male and four female rats that received 60 mg/kg died before the end of the studies. There were no chemical-related deaths in mice. Final mean body weights of male rats that received 15 or 30 mg/kg and female rats that received 60 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 60 mg/kg were significantly lower than controls. Relative and absolute liver weights in both sexes of rats and mice were increased in groups that received furan, as were relative and absolute kidney weights in female rats that received furan. Thymus weights were decreased in all groups of rats that received furan. Toxic lesions of the liver (bile duct hyperplasia, cholangiofibrosis, cytomegaly and degeneration of hepatocytes, and nodular hyperplasia of hepatocytes) were associated with furan administration in all dose groups of rats; the severity of the lesions increased with dose. Kidney lesions (tubule dilatation and necrosis of tubule epithelium) were present in rats that received 30 or 60 mg/kg. Thymic atrophy and testicular or ovarian atrophy were also observed in rats exposed to 60 mg/kg furan. Toxic liver lesions (cytomegaly, degeneration, and necrosis of hepatocytes) were also present in all groups of furan-exposed mice. Bile duct hyperplasia and cholangiofibrosis were observed in groups of mice receiving 30 or 60 mg/kg. Doses selected for the 2-year studies of rats and mice were based on the hepatotoxicity associated with exposure to furan. 2-Year Studies: Groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 years. After 9 and 15 months of chemical exposure, 10 rats per group were evaluated for the presence of treatment-associated lesions. Groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 years. Body Weight and Survival: Mean body weights of male rats that received 8 mg/kg furan were lower than controls from approximately week 73 to the end of the study. Survival of male and female rats that received 8 mg/kg was lower than controls from approximately week 85 to the end of the studies as a result of moribund condition associatedassociated with liver and biliary tract neoplasms and mononuclear cell leukemia. Mean body weights of male and female mice that received 15 mg/kg furan were lower than controls during the studies. Survival of low- and high-dose male and high-dose female mice was lower than controls from approximately week 80 to the end of the studies as a result of moribund condition associated with liver neoplasms. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred in all groups of dosed rats (males: control, 0/50; low dose, 43/50; mid dose, 48/50; high dose, 49/50; females: 0/50; 49/50; 50/50; 48/50) and was present in many rats of each sex at the 9- and 15-month interim evaluations (9-month: males - 0/10, 5/10, 7/10, 10/10; females - 0/10, 4/10, 9/10, 10/10; 15-month: males - 0/10, 7/10, 9/10, 6/10; females - 0/10, 9/10, 9/10, 7/10). Hepatocellular adenomas or carcinomas (combined) were significantly increased in male rats after 2 years of chemical administration (1/50, 5/50, 22/50, 35/50) and hepatocellular adenomas were significantly increased in female rats (0/50, 2/50, 4/50, 7/50); hepatocellular neoplasms were not observed at the 9- or 15-month interim evaluations. Increased incidences of numerous nonneoplastic liver lesions were present in rats administered furan. These lesions included biliary tract fibrosis, hyperplasia, chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis. The incidence of mononuclear cell leukemia was increased in male and female rats that received 4 or 8 mg/kg furan (males: 8/50, 11/50, 17/50, 25/50; females: 8/50, 9/50, 17/50, 21/50); the incidence in the 8 mg/kg groups of each sex exceeded the historical control ranges for corn oil gavage studies. The severity of nephropathy increased with dose and the incidence was significantly increased in all groups of dosed rats; this increased severity was accompanied by an associated increased incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism). The incidence of forestomach hyperplasia was increased in male and female rats (males: 1/50, 4/49, 7/50, 6/50; females: 0/50, 2/50, 5/50, 5/50) and the incidence of subacute inflammation of the forestomach was increased in female rats (0/50, 1/50, 5/50, 6/50). No forestomach neoplasms were observed in males; a squamous papilloma was present in one low-dose female. The incidences of hepatocellular adenomas and carcinomas were significantly increased in mice receiving furan (males: adenoma - 20/50, 33/50, 42/50; carcinoma - 7/50, 32/50, 34/50; females: adenoma - 5/50, 31/50, 48/50; carcinoma - 2/50, 7/50, 27/50). The incidences of numerous nonneoplastic hepatocellular lesions were increased in dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal hyperplasia, and cytoplasmic vacuolization and biliary tract dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in low- and high-dose male and in high-dose female mice (benign pheochromocytoma: males - 1/49, 6/50, 10/50; females - 2/50, 1/50, 6/50). The incidences of squamous papilloma, focal inflammation, and papillary hyperplasia of the forestomach were increased in male mice (squamous papilloma: 0/49, 1/50, 3/50; focal inflammation: 9/49, 13/50, 21/50; papillary hyperplasia: 7/49, 14/50, 22/50). Stop-Exposure Study: A separate 2-year study was conducted in which 50 male rats were administered 30 mg/kg furan in corn oil by gavage 5 days per week for 13 weeks and then maintained for the remainder of the 2 years without additional furan administration. Groups of 10 animals were evaluated for the presence of treatment-related lesions at the end of the 13-week period of furan administration and at 9 and 15 months. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred with an overall incidence of 100&percnt; (40/40) and hepatocellular carcinoma occurred with an overall incidence of 15&percnt; (6/40) in stop-exposure male rats that survived at least 9 months. Cholangiocarcinoma was observed in all 10 males at both the 9-month and 15-month interim evaluations. Hepatocellular carcinoma was first observed in 2 males at the 15-month interim evaluation. Genetic Toxicology: Furan was negative for induction of gene mutations in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 in the presence and the absence of exogenous metabolic activation (S9). Furan was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered either by feeding or by injection. In vitro tests for genotoxicity in mammalian cells, however, were positive. Furan induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9, and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, with and without S9. Furan administered to male B6C3F1 mice by intraperitoneal injection induced chromosomal aberrations but not sister chromatid exchanges in bone marrow cells. Conclusions: Under the conditions of these 2-year gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. Nonneoplastic liver lesions associated with furan administration in rats and mice included biliary tract fibrosis, hyperplasia, inflammation, and proliferation, as well as hepatocellular cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats, increased severity of nephropathy with an associated increased incidence of parathyroid hyperplasia was associated with exposure to furan. Synonyms: Divinylene oxide, tetrole, furfuran, oxole, 1,4-epoxy-1,3-butadiene, axole, oxacyclopentadiene
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PMID:Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice(Gavage Studies). 1262 16

Quercetin is a member of a group of naturally occurring compounds, the flavonoids, which have a common flavone nucleus composed of two benzene rings linked through a heterocyclicpyrone ring. Quercetin is found in various plants, food products, and dyes of natural origin. The estimated average daily intake of quercetin by an individual in the United States is 25 mg. The Food and Drug Administration nominated quercetin for toxicity and carcinogenicity studies in the rat because it is a chemical that is widely distributed in foods. Quercetin was administered to rats by dosed feed since human exposure is by dietary consumption. Information in the literature showed that quercetin administered in the diet to rats at levels up to approximately 4% caused a minor body weight effect, whereas higher dose levels produced greater than 10% reduction in body weight gains relative to controls. Based on this information, the NTP 2-year studies were conducted by administering 0, 1,000, 10,000, or 40,000 ppm quercetin (>95% pure) in feed to groups of 50 male and female rats for 104 weeks. Ten additional animals per dose group were evaluated at 6 and 15 months. Body Weight, Survival, and Clinical Findings in the 2-Year Studies: Body weights of exposed male and female rats given 1,000 and 10,000 ppm were within 5% of controls throughout the studies. Reduced body weight gain in male and female rats receiving 40,000 ppm was observed by week 15 and the final mean body weights were 87% of controls at week 104. Survival and feed consumption were similar among exposed and control groups throughout the studies. The average amounts of quercetin consumed per day by the 1,000, 10,000 and 40,000 ppm dose groups after week 52 were 40, 400, and 1,900 mg/kg of body weight. Nonneoplastic and Neoplastic Effects in the 2-Year Studies: In male rats, the principal toxic effects associated with the dietary administration of quercetin for 2 years were observed in the kidney. There were dose-related increases in the severity of chronic nephropathy (control, 2.7; low-dose, 2.7; mid-dose, 3.0; high-dose, 3.2) and a slight increased incidence in focal hyperplasia of the renal tubule epithelium (1/50; 2/50; 3/50; 4/50). Parathyroid hyperplasia, indicative of renal secondary hyperparathyroidism, also increased incidence in dosed male rats (1/43, 6/45, 6/43, 17/43). The evaluation of single sections from the left and right kidneys revealed renal tubule adenomas in three male rats and adenocarcinomas in another male rat receiving 40,000 ppm quercetin; none were seen in the controls. Examination of additional step sections of the male rat kidney identified additional hyperplasia and adenomas in all dose groups (hyperplasia: 2/50, 2/50, 6/50, 8/50; adenoma: 1/50, 2/50, 7/50, 6/50). The overall incidence of renal tubule adenoma or adenocarcinoma combined in male rats was 1/50 in controls and 9/50 in the high-dose group. There was no apparent effect of quercetin on the kidney of female rats. A single renal tubule adenoma was seen in a female receiving 10,000 ppm; this neoplasm was not considered biologically significant. There was a statistically significant, dose-related decrease in the incidence of mammary gland fibroadenomas in exposed female rats (29/50, 27/50, 16/50, 9/50), which may in part be attributed to lower body weight gains. There was a treatment-related accumulation of yellow-brown granular pigment adsorbed to or absorbed by the epithelial cells of the glandular stomach, ileum, jejunum, and, to a lesser extent, the duodenum and colon. The severity of the pigmentation in these tissues increased with increased length of exposure. There were no other lesions considered to be related to chemical administration. Genetic Toxicology: Quercetin induced gene mutations in Salmonella typhimurium strains TA100 and TA98 with and without exogenous metabolic activation (S9). Positive results were also obtained in tests with and without S9 for induction of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. Conclusions: Under the conditionslls. Conclusions: Under the conditions of these 2-year feed studies there was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas. There was no evidence of carcinogenic activity of quercetin in female F344/N rats receiving 1,000, 10,000 or 40,000 ppm. The incidence of renal tubule hyperplasia and the severity of nephropathy were increased in exposed male rats. Synonyms: C.I. Natural Yellow 10; C.I. 75670; Cyanidelonon 1522; Flavin Meletin; Quercetine; Quercetol; Quertin; Quertine; Sophoretin; Xanthaurine; 3,3',4',5,7-Pentahydroxyflavone; 3,5,7,3',4'-Pentahydroxyflavone; 2-(3,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one
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PMID:Toxicology and Carcinogenesis Studies of Quercetin (CAS No. 117-39-5) in F344 Rats (Feed Studies). 1262 21

Acetaminophen is a widely consumed analgesic found in several nonprescription pharmaceuticals. Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity >99%) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-DAY STUDIES: Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES: Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES: Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male. GENETIC TOXICOLOGY: Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 witr TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice. Synonyms: 4-Hydroxyacetanilide, N-Acetyl-p-aminophenol, Paracetamol
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PMID:NTP Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344 Rats and B6C3F1 Mice (Feed Studies). 1263 65

Hydrochlorothiazide is a diuretic active at the distal convoluted tubule and collecting duct. Toxicology and carcinogenesis studies were conducted by feeding diets containing hydrochlorothiazide (USP grade, greater than 98% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 15 days, 13 weeks, 1 year, or 2 years. Additional studies were performed to evaluate teratologic effects in CD(R). rats and CD(R).-1 mice. Genetic toxicology studies were performed with Salmonella, Chinese hamster ovary (CHO) cells, mouse lymphoma cells, and Drosophila. Fifteen-Day and Thirteen-Week Studies: All rats and mice lived to the end of the 15-day studies (dietary concentrations of 0 and 3,125-50,000 ppm). The final mean body weights of all dosed rat groups were 5%-11% lower than those of controls. The final mean body weights of the groups of male mice that received 6,250-50,000 ppm were 10%-14% lower than that of controls. The final mean body weights of dosed and control female mice were similar. Calculi were seen in the urinary bladder of 2/5 male and 2/5 female mice at 50,000 ppm and in 1/5 male and 1/5 female mice at 25,000 ppm. All rats lived to the end of the first 13-week studies (dietary concentrations of 0 and 3,125-50,000 ppm). Final body weights of dosed rats were 7%-16% lower than those of controls. Mineralization in the kidney was observed in all dosed rats and because of this, additional 13-week studies in rats were conducted at lower dietary concentrations. All rats lived to the end of the second 13-week studies (dietary concentrations of 0 and 250-4,000 ppm). The final mean body weights of all dosed rat groups were 5%-10% lower than those of controls. Renal mineralization was dose related and judged to be minimal to mild at the lowest dose. In the 13-week studies in mice, 7/10 males and 1/10 females that received 50,000 ppm hydrochlorothiazide died. The final mean body weights of mice that received 50,000 ppm were 11% lower than those of controls for males and females. Calculi were seen in the urinary bladder of mice that received hydrochlorothiazide at 12,500 ppm and above. Nephrosis occurred with dose-related incidences in mice receiving 12,500 ppm and above. Based on these results, 2-year studies were conducted by feeding diets containing 0, 250, 500, or 2,000 ppm hydrochlorothiazide to groups of 50 male and 50 female rats for 105-106 weeks. Diets containing 0, 2,500, or 5,000 ppm hydrochlorothiazide were fed to groups of 50 male and 50 female mice for 103-104 weeks. Ten additional rats per sex and dose group were placed on study and killed at 1 year for blood-clotting studies and histopathologic examination. Effects in the One-Year Studies: One of 10 female rats in the 1-year study group that received 2,000 ppm died with internal hemorrhage. In addition, evidence of hemorrhage was found in 11 of the 16 dosed female rats that died during the first year of the 2-year study. Hematologic analyses revealed no compound-related effects; however, activated partial thromboplastin times (APTTs) were highly variable and were lengthened in some dosed male rats. No effects on APTTs were seen for females, and no effects on prothrombin times or on the fibrinogen content of plasma were observed for dosed male or female rats. Nephropathy occurred in dosed and control rats, and the severity was judged to be greater in dosed male and high dose female rats. Increased incidences of mild focal renal mineralization were also seen in mid and high dose male rats and dosed female rats. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were 8%-25% lower than those of controls. Mean body weights of dosed and control mice were similar throughout the studies. No significant differences in survival were observed between rats or mice of either sex (rats-- male: control, 18/50; low dose, 16/50; mid dose, 9/50; high dose, 11/50; female: 31/50; 26/50; 30/50; 27/50; mice--male: control, 43/50; low dose, 42/50; high dose, 43/50; female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a lar female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a large number of animals were killed in a moribund condition late in the study. The average daily feed consumption by dosed rats was 89&percnt;-94&percnt; that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 11, 23, or 89 mg/kg for low, mid, or high dose rats. The average daily feed consumption by dosed mice was 100&percnt;-105&percnt; that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 280 or 575 mg/kg for low dose or high dose mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred in nearly all male and female rats, but the severity of this disease was greater in dosed rats, as evidenced by increases in renal cysts and epithelial hyperplasia of the renal pelvis in dosed rats shown in the following table (see page 4 of the Technical Report). Mineralization was observed at increased incidences in dosed male and dosed female rats. Changes associated with or secondary to renal injury were increased in dosed rats. These lesions included parathyroid hyperplasia, fibrous osteodystrophy of bone, and mineralization of multiple organs. Adenomas or carcinomas (combined) of the Zymbal gland in male rats occurred in 1/50 control, 1/49 low dose, 2/50 mid dose, and 4/50 high dose animals. The historical incidence of Zymbal gland neoplasms in untreated F344/N rats is 19/1,936 (1.0&percnt;), and the highest observed control group incidence is 4/50. This marginal increase was not considered to be chemically related. The incidences of fibroadenomas of the mammary gland were decreased in dosed female rats (30/50; 12/50; 11/49; 5/50). The incidence of hepatocellular neoplasms was increased in high dose male mice (adenomas or carcinomas, combined: control, 7/48; low dose, 10/49; high dose, 21/50). The historical incidence of hepatocellular adenomas or carcinomas (combined) is 609/2,032 (30&percnt;) in untreated controls. Teratology: Hydrochlorothiazide produced no teratologic effects in the offspring of CD®. rats or CD®.-1 mice after gavage administration to pregnant females on day 6 through day 15 of gestation. Genetic Toxicology: In the absence of exogenous metabolic activation, hydrochlorothiazide produced an equivocal increase in revertant colonies in Salmonella typhimurium strain TA98; no increase was observed in strains TA100, TA1535, or TA1537 with or without activation. Hydrochlorothiazide induced an increase in trifluorothymidine (Tft)-resistant cells in a mouse lymphoma L5178Y/TK+/- assay without exogenous metabolic activation; this assay was not performed with activation. In cultured CHO cells, hydrochlorothiazide induced sister chromatid exchanges (SCEs) in the presence and absence of exogenous metabolic activation but did not induce chromosomal aberrations. Hydrochlorothiazide did not increase the frequency of sex-linked recessive lethal mutations when administered by feeding or injection to adult male Drosophila melanogaster. Audit: The data, documents, and pathology materials from the 2-year studies of hydrochlorothiazide have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of hydrochlorothiazide for male or female F344/N rats given feed containing 250, 500, or 2,000 ppm hydrochlorothiazide. There was equivocal evidence of carcinogenic activity of hydrochlorothiazide for male B6C3F1 mice, based on increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given diets containing 2,500 or 5,000 ppm hydrochlorothiazide. Chronic renal disease was more severe in rats administered hydrochlorothiazide, and increased incidences of secondary lesions (parathyroid hyperplasia, fibrous osteodystrophy, and mineralization in multiple organs) occurred in dosed rats. Synonym: 6-chloro-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sulfonamide 1,1-dioxide Trade Names: Aquarius; Bremil; Chlorzide; Cidrex; Dichlorosal; Dichlotride; Diclotride; Direma; Disalunil; Esidrix; Fluvin; Hidroronol; Hydril; Hydro-Aquil; Hydro-Diuril; Hydrosaluric; Hydrothide; Hypothiazide; Ivaugan; Jen-Diril; Maschitt; Nefrix; Neo-Codema; Neoflumen; Oretic; Panurin; Ro-Hydrazide; Thiaretic; Thiuretic; Urodiazin; Vetidrex
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PMID:Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 84

The aim of this study was to evaluate the efficacy of 99mTc-MIBI and 123I subtraction scintigraphy for the detection of abnormal parathyroid glands to be referred for surgical treatment. Thirty-nine consecutive patients, including 35 primary and four secondary cases of hyperparathyroidism, were evaluated. 99mTc-MIBI/123I subtraction scintigraphy (MIBI/I) was performed on all patients, and the results were compared with delayed images of 99mTc-MIBI (D-MIBI), magnetic resonance imaging (MRI) and ultrasonography (US). The overall sensitivity of MIBI/I, MRI, US and D-MIBI was 55.9%, 43.4%, 50.8% and 39.0%, respectively. In cases of single-gland disease, the sensitivity of MIBI/I, MRI, US and D-MIBI was 62.1%, 48.3%, 55.2% and 44.8%, respectively. In cases of multi-gland disease, the sensitivity of MIBI/I, MRI, US and D-MIBI was 50.0%, 37.5%, 46.7% and 36.7%, respectively. In cases of parathyroid adenoma, the sensitivity of MIBI/I, MRI, US and D-MIBI was 71.4%, 50.0%, 71.4% and 50.0%, respectively. In cases of parathyroid hyperplasia, the sensitivity of MIBI/I, MRI, US and D-MIBI was 55.2%, 42.3%, 50.0% and 39.7%, respectively. It is concluded that 99mTc-MIBI/123I subtraction is more useful than the delayed imaging of 99mTc-MIBI, MRI and US.
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PMID:Parathyroid scintigraphy with 99mTc-MIBI and 123I subtraction: a comparison with magnetic resonance imaging and ultrasonography. 1281 93

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