Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Riddelliine is a naturally occurring pyrrolizidine alkaloid, a class of compounds occurring in rangeland plants of the genera Crotalaria, Amsinckia, and Senecio. Two-week and 13-week rodent toxicity studies of riddelliine were conducted because riddelliine can be a contaminant of foodstuffs, such as meat, grains, seeds, milk, herbal tea, and honey. In addition to histopathology, evaluations included clinical pathology and reproductive toxicity. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and of the induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Riddelliine was also evaluated in vivo for the induction of micronuclei in mouse bone marrow and in peripheral blood and for the induction of S-phase synthesis and unscheduled DNA synthesis in the liver of rats and mice. In the 2-week studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered riddelliine in 0.1 M phosphate buffer by gavage at dose levels of 0, 0. 33, 1.0, 3.3, 10, or 25 mg/kg body weight five times per week, for a total of 12 doses. Four of five male rats in the 25 mg/kg group died or were killed moribund before the end of the study. Mean body weight gains of male rats in the 10 and 25 mg/kg groups were depressed. No deaths or body weight effects were observed in female rats. Male rats had dose-related hemorrhagic centrilobular hepatic necrosis, hepatocytic karyomegaly and cytologic alterations, pulmonary hemorrhage and/or edema, splenic extramedullary hematopoiesis, and pancreatic edema. Female rats exhibited fewer and less severe lesions than identically treated male rats. Heart weights of treated male and female rats were lower than those of the controls. No deaths or effects on body weight were observed in treated mice. Dose-related increases in absolute and relative liver weights and increased incidences of hepatic cytomegaly were the only treatment-related findings in male and female mice administered riddelliine. In the 13-week studies, groups of 20 male and 20 female F344/N rats and B6C3FI mice were administered riddelliine in 0.1 M phosphate buffer by gavage five times per week for 13 weeks. Rats received 0, 0.1, 0.33, 1.0, 3.3, or 10 mg/kg and mice received 0, 0.33, 1.0, 3.3, 10, or 25 mg/kg. Ten animals from each dose group were killed after 13 weeks of treatment. The remaining 10 animals in each dose group were observed without further treatment for up to 14 weeks; five animals from each dose group were killed after 7 weeks of recovery, and the remaining five animals per dose group were killed at the end of the 14-week recovery period. During the 13-week treatment period, 19 of 20 male rats in the high-dose group died; all others survived. Body weight gains were decreased with increasing dose at Week 13. During the 14-week recovery period, all male rats survived, but five high-dose females died. Mean body weight gains of dosed and control male rats were similar throughout the 1 4-week recovery period; the final mean body weights of the treated males approached the final mean body weight of the controls. Similarly, mean body weight gains among the treated female rats were similar to the control value at the end of the 14- week recovery period. However, the final mean body weight of female rats given 1.0 or 3.3 mg/kg remained lower than that of controls at the end of the 14-week recovery period. In the 13-week study, the most significant treatment-related histopathologic lesions in rats occurred in the liver and included hepatocyte cytomegaly and karyomegaly, cytoplasmic vacuolization, centrilobular necrosis, mixed inflammatory cell infiltration, and bile duct hyperplasia. Vascular lesions in the kidneys and lungs were observed in most high- dose rats after 13 weeks of riddelliine administration. Additional lesions were found in the heart, spleen, kidneys, and pancreas at 13 weeks. At the end of the 14-week recovery period, hepatocyte karyomegaly, cytomegaly, and cytoplasmic vacuolization persisted. In addition, the incidence of bile duct hyperplasia was markedly increased in dosed female rats, and foci of cytologic alteration or hyperplastic hepatocytes were observed in dosed rats that were allowed to recover for up to 14 weeks. Adenomas of the liver occurred in 2 of 10 females in the 10 mg/kg group at 13 weeks and in one of five females in this group after the 14-week recovery period; no adenomas were found in the livers of control females. Serum activities of alkaline phosphatase in male rats and sorbitol dehydrogenase in female rats increased with increasing dose. Reticulocyte counts consistently increased and platelet counts consistently decreased with increasing dose in treated male and female rats. The clinical pathology findings were indicative of liver damage and erythrocyte and platelet sequestration. In mice in the 13-week study, no deaths related to riddelliine treatment occurred. Body weight gains were depressed at the two highest dose levels (10 and 25 mg/kg); the depression in body weight persisted throughout the 14- week recovery period. Dose-related increases in erythrocyte counts in male mice and in reticulocyte counts in female mice were observed. Dose-related decreases in platelet counts were also observed in both males and females. Centrilobular cytomegaly in the liver was noted at 13 weeks in males and females administered 25 mg/kg riddelliine; this lesion persisted through the recovery period in females. At the end of the 14-week recovery period, bile duct hyperplasia was seen in the liver in high-dose female mice. Epithelial hyperplasia of the forestomach was noted in male and female mice in the 10 and 25 mg/kg groups after 13 weeks of treatment, but this lesion became less severe during the recovery period. In male rats administered up to 3.3 mg/kg and in male mice administered up to 25 mg/kg for 13 weeks, riddelliine did not adversely affect any of the reproductive end points evaluated. In female rats given 10 mg/kg and in female mice given 25 mg/kg, the length of the estrous cycle was increased. However, no unequivocal adverse effects were noted on fertility, pup growth and survival, or weight gain of dams during pregnancy during the mating trial in rats, although mean body weights of dams given 0.1 or 1.0 mg/kg were significantly lower than the mean body weight of the controls throughout gestation and lactation. In contrast, riddelliine administered at a dose of 25 mg/kg was toxic to the dams in the mouse mating trial, resulting in lower body weights at the beginning of gestation and throughout lactation. Administration of 25 mg/kg riddelliine to mouse dams also affected fetal growth and survival; the average live litter size was significantly reduced, the number of pups born dead was increased, and the average pup weight was reduced throughout the 21-day postpartum period. Riddelliine was mutagenic in Salmonella typhimurium strain TA100 with, but not without, S9 activation; results of mutagenicity testing were negative in strains TA97, TA98, and TA1535. Riddelliine induced sister chromatid exchanges in Chinese hamster ovary (CHO) cells with and without S9. Chromosomal aberrations were induced in CHO cells only in the presence of S9. The frequency of micronucleated erythrocytes in mouse peripheral blood samples was not elevated after 4 or 13 weeks of daily gavage treatments; however, a weakly positive response was noted in the peripheral blood and bone marrow of male mice administered a single, high dose of riddelliine by gavage. Unscheduled DNA synthesis was detected in cultured hepatocytes from male and female rats and mice following 5 or 30 days of riddelliine treatment by gavage. In addition, an increase in S-phase DNA synthesis was observed in cultured hepatocytes of male and female rats treated for either time period. In summary, the administration of riddelliine to rodents by gavage for up to 13 weeks resulted in a spectrum of neoplastic and nonneoplastic effects similar to those previously described for other pyrrolizidine alkaloids. Rats were found to be somewhat more sensitive than mice, and males more sensitive than females, to the toxic effects of riddelliine. The no-observed-adverse-effect level (NOAEL) for histopathologic changes in the 13-week studies was 3.3 mg/kg body weight for mice and 0.1 mg/kg body weight for rats. The liver was the primary target of riddelliine-induced injury that resulted in lesions characterized by cytomegaly and cytologic alteration in rats and mice and also by marked necrotic and proliferative changes in rats. Riddelliine is carcinogenic to female F344/N rats, based on the occurrence of hepatocellular adenomas. Synonyms: 13,19-didehydro-12,18-dihydroxy senecionan-11,16- dione; trans-15-ethylidine-12b-hydroxy-12a-hydroxymethyl-13-methylenesenec-1-enine; 3-ethylidine-3,4,5,6,9,11,13,14,14a,14b-decahydro-6-hydroxy-6-(hydroxymethyl)-5-methylene (1,6)di-oxacyclododecino(2,3,4-gh)-pyrrolizidine-2,7-dione.
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PMID:NTP technical report on the toxicity studies of Riddelliine (CAS No. 23246-96-0) Administered by Gavage to F344 Rats and B6C3F1 Mice. 1220 79

An autopsy case with a widespread mucosal carcinoma of the biliary tree was reported. A biochemical profile of the bile duct damage was noticed in a woman in her seventies during a gastric examination. Imaging procedures depicted irregular dilatations of intrahepatic bile ducts with a bead-like appearance. Elevated levels of serum alkaline phosphatase and gamma-glutamyltransferase with a negative antimitochondrial antibody persisted. The patient was diagnosed as primary sclerosing cholangitis, she was followed up for 4 years under preservative therapies, and died of anasarca and heart failure. Post-mortem examination showed a diffuse mucosal carcinoma of both intrahepatic and extrahepatic biliary passages including the gallbladder with a minimal invasion and scattered foci of adenoma-like area in part. There was no evidence of gallstones or pre-existing sclerosing cholangitis. The striking features of the tumor were extensive papillary growth, mucus secretion and irregular dilatation of bile ducts. The tumor may bear biological and morphological homology with intraductal papillary mucinous tumor of the pancreas.
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PMID:Diffuse mucosal carcinoma of intrahepatic and extrahepatic bile ducts including gallbladder. 1258 48

4,4'-Thiobis(6- t -butyl- m -cresol) (TBBC) is used in the rubber and plastics industries as an antioxidant. TBBC is also used as a stabilizer in polyethylene and polyolefin packaging materials for foodstuffs. Toxicology and carcinogenesis studies were conducted by administering TBBC (99% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 15-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 2,500, 5,000, 10,000 or 25,000 ppm TBBC for 15 days. Rats given to 1,000, 2,500, 5,000, or 10,000 ppm received approximate doses of 95, 235, 335, or 365 mg TBBC per kilogram body weight per day (males) or 85, 220, 325, or 270 mg/kg per day (females). Approximate doses for rats receiving 25,000 ppm could not be calculated due to early deaths. All 25,000 ppm rats and three male and four female 10,000 ppm rats died. Surviving rats in the 10,000 ppm groups had a significant weight loss and the final mean body weights of 5,000 and 10,000 ppm male and female rats were significantly lower than those of the controls. Male and female rats exposed to 5,000, 10,000, or 25,000 ppm TBBC consumed markedly less feed than the controls. Diarrhea occurred in 5,000, 10,000, and 25,000 ppm males and females. The principal lesions attributed to the administration of TBBC were renal papillary and tubule necroses which occurred in 10,000 ppm rats. Focal necrosis or erosions of the glandular stomach also occurred in some 10,000 ppm rats. Changes observed in the thymus and spleen were attributed to debilitation or stress; bone marrow depletion was attributed to nutrient deficiency accompanying weight loss. 15-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 1,000, 2,500, 5,000, 10,000, or 25,000 ppm TBBC for 15 days. Mice given 1,000, 2,500, or 5,000 ppm received approximate doses of 285, 585, or 475 mg TBBC per kilogram body weight per day (males) or 360, 950, or 1,030 mg/kg per day (females). Approximate doses for mice given 10,000 or 25,000 ppm could not be calculated due to early deaths. All 10,000 and 25,000 ppm mice died, as did eight males and eight females given 5,000 ppm. A significant weight loss occurred in surviving 5,000 ppm males and females and the final mean body weights of 2,500 ppm females and 5,000 ppm males and females were significantly lower than those of the controls. Feed consumption by mice given 5,000, 10,000, or 25,000 ppm was markedly reduced. Diarrhea occurred in all 25,000 ppm mice and in most male and female mice given 5,000 or 10,000 ppm. Renal tubule necrosis occurred in eight males and three females in the 5,000 ppm groups. Lymphocytic depletion of Iymphoid tissues in many 5,000 ppm males and females was attributed to debilitation and stress or to nutrient deficiency accompanying weight loss. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 250, 500, 1,000, 2,500, or 5,000 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 60, 165, or 315 mg TBBC per kilogram body weight per day (males) or 15, 35, 70, 170, or 325 mg/kg per day (females). All rats survived to the end of the study. The final mean body weight of 5,000 ppm males was 40% lower than that of the controls; the final mean body weight of 5,000 ppm females was 27% lower than that of the controls. Feed consumption by male and female rats exposed to 5,000 ppm TBBC was markedly lower than that by the controls throughout the study. The absolute and relative liver weights of 5,000 ppm females were significantly greater than those of the controls. Serum alkaline phosphatase (ALP) levels were significantly higher in 2,500 and 5,000 ppm males and slightly higher in 5,000 ppm females. Serum alanine aminotransferase levels were significantly higher in 2,500 and 5,000 ppm males and females. Hematocrit and hemoglobin concentrations and mean erythroions and mean erythrocyte volume (MCV) values were significantly lower in 1,000, 2,500, and 5,000 ppm males than in controls; MCV values were also significantly lower in 5,000 ppm females. A dose-related significant increase in forelimb and hindlimb grip strength was observed in exposed male and female rats. Histopathologic findings in the liver of 2,500 and 5,000 ppm males and females included hypertrophy of Kupffer cells, bile duct hyperplasia, and individual cell necrosis of hepatocytes; centrilobular hepatocyte hypertrophy also occurred in males and females exposed to 5,000 ppm TBBC. Macrophages were increased in size and number in the mesenteric Iymph nodes of males and females exposed to 5,000 ppm, and to a lesser extent in 2,500 ppm male and female rats. Pigmentation and degeneration of the renal cortical tubule epithelial cells was also present in males and females in the 2,500 and 5,000 ppm groups; cortical tubule necrosis occurred in 5,000 ppm males and females. 13-WEEK STUDY IN MICE: Groups of up to 10 male and 10 female B6C3F1 mice were fed diets containing 0, 100, 250, 500, 1,000, or 2,500 ppm TBBC for 13 weeks. These exposure levels delivered approximate doses of 15, 30, 65, 145, or 345 mg TBBC per kilogram body weight per day (males) or 10, 35, 60, 165, or 340 mg/kg per day (females). All mice survived to the end of the study. The final mean body weights of 2,500 ppm males and of 500,1,000, or 2,500 ppm females were significantly lower than those of the controls. Feed consumption by 2,500 ppm males averaged 24% lower than that by controls through week 3 and was similar to that by controls for the remainder of the study. Feed consumption by females receiving 2,500 ppm averaged 27% less than that by the controls during most of the study. The absolute and relative liver weights of males and females exposed to 2,500 ppm TBBC were slightly but significantly greater than those of the controls. Males exposed to 500, 1,000, or 2,500 ppm and females exposed to 2,500 ppm had significantly increased absolute and relative spleen weights. No clinical findings in mice were considered chemical related. Hematocrit concentrations and erythrocyte counts of males receiving 1,000 or 2,500 ppm were significantly less than those of the controls; hemoglobin concentration in males receiving 2,500 ppm was significantly less and mean erythrocyte volume was significantly less in males receiving 2,500 ppm. Females in the 1,000 and 2,500 ppm groups had significantly decreased hematocrit concentrations and erythrocyte counts; 2,500 ppm females also had significantly decreased hemoglobin concentrations and mean erythrocyte volumes. Kupffer cell hypertrophy, bile duct hyperplasia, and an increase in size and number of macrophages in mesenteric Iymph nodes were present in 2,500 ppm male and female mice. 2-YEAR STUDY IN RATS: Doses selected for the 2-year study of TBBC were based on the lower body weights and liver and kidney toxicity observed at 5,000 ppm in the 13-week study. Groups of 115 male and 75 female F344/N rats were fed diets containing 0, 500, 1,000, or 2,500 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in a daily ingestion of TBBC of approximately 20, 40, or 100 mg/kg body weight for males and 20, 45, or 120 mg/kg body weight for females. Hematology, clinical chemistry, and urinalysis evaluations were performed on 15 male and 15 female rats from each group at 3, 9, and 15 months. Also at 15 months, an additional 10 male and 10 female rats from each group were evaluated for histopathology, hematology, and clinical chemistry. Forty male rats per group were evaluated for neurotoxic effects. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates and mean body weights of exposed male and female rats were generally similar to those of the controls. The mean body weights of 2,500 ppm male rats were slightly lower than those of the controls throughout the study. At week 65, the mean body weight of 2,500 ppm females was 14% lower than that of the controls, but the final mean body weight of this group was 6% lower than that of the control group. Feed consumption, behavior, and general health and appearance of exposed male and female rats were similar to those of the controls. Hematology and Clinical Chemistry: Results of the hematology evaluation were not uniformly consistent at 3, 9, and 15 months in one set of rats, nor were they consistent between the two sets of rats evaluated at 15 months. Slight but significant decreases in hematocrit levels, hemoglobin concentrations, and erythrocyte counts were observed in the 1,000 and 2,500 ppm groups in one set of males at 15 months. Similar significant decreases in hematocrit level and hemoglobin concentration occurred in 2,500 ppm females at 9 months. Mean erythrocyte hemoglobin and mean erythrocyte hemoglobin concentration of 2,500 ppm females were also significantly lower than those of controls at 9 months and in both sets of female rats evaluated at 15 months. Platelet counts of 2,500 ppm male and female rats were slightly but significantly higher than those of controls at 3 and 9 months. Platelet counts were also slightly but significantly increased in 2,500 ppm males of one set evaluated at 15 months, and in 2,500 ppm females of the second set evaluated at 15 months. Serum activities of alkaline phosphatase, alanine aminotransferase, and sorbitol dehydrogenase in 2,500 ppm males were significantly greater than those in the controls at 3, 9, and 15 months. Alkaline phosphatase activities in both sets of 1,000 ppm males evaluated at 15 months were also significantly greater than those of controls. Serum activities of alanine aminotransferase and sorbitol dehydrogenase in 2,500 ppm females were also significantly greater than those in controls at 3, 9, and 15 months. Neurotoxicity Findings: There were no significant inhibitory effects of TBBC on motor nerve excitability or conduction, neuromuscular transmission, or muscle contractility. There were no microscopic lesions in the sciatic nerve, quadriceps muscle, or teased nerve preparations of sciatic nerve that could be attributed to TBBC administration. Pathology Findings: At the 15-month interim evaluation, the absolute and relative liver weights of 2,500 ppm female rats were significantly greater than those of controls; at 15 months and at the end of the study, the incidences of Kupffer cell hypertrophy, hepatocyte cytoplasmic vacuolization, and mixed cell foci were also significantly increased. At the end of the study, the incidence of hepatocellular fatty change was significantly increased in 2,500 ppm females. The incidence of Kupffer cell hypertrophy was significantly increased in 2,500 ppm males at 15 months and at 2 years; the incidence of cytoplasmic vacuolization was significantly increased in all exposed males at 15 months but only moderately increased in 1,000 and 2,500 ppm males at 2 years; the incidence of basophilic foci was significantly increased in 2,500 ppm males at 15 months and the incidence of mixed cell foci was significantly increased in 1,000 and 2,500 ppm male rats at 2 years. The incidences of hepatocellular adenoma or carcinoma (combined) in exposed male rats were not significantly greater than that in the controls (0 ppm, 1/50; 500 ppm, 3/50; 1,000 ppm, 3/50; 2,500 ppm, 5/49), were within the historical control range, and were not considered chemical related. The severity of nephropathy was significantly increased in 2,500 ppm female rats. There was a significant negative trend in the incidence of mammary gland fibroadenoma, adenoma, or carcinoma (combined) in female rats (32/50, 24/50, 11/50, 16/50), and the incidences of fibroadenoma in 1,000 and 2,500 ppm females were significantly less than that of the controls. 2-YEAR STUDY IN MICE: Because of the reduction in body weights, the increase in liver and spleen weights, and the accompanying histopathologic changes in the liver of 2,500 ppm male and female mice in the 13-week study, the doses selected for the 2-year study were 250, 500, and 1,000 ppm. Groups of 80 male and 80 female mice were fed diets containing 0, 250, 500, or 1,000 ppm TBBC for 2 years. Based on average daily feed consumption, these exposure levels resulted in the daily ingestion of approximately 30, 60, or 145 mg TBBC/kg body weight for males and 45, 110, or 255 mg TBBC/kg body weight for females. Nine or 10 animals from each exposure group were evaluated at 3, 9, and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed male and female mice were similar to those of the controls. The final mean body weights of male and female mice exposed to 1,000 ppm were 8% and 18% lower than those of the controls, respectively. The final mean body weights of females exposed to 250 or 500 ppm were 8% to 9% lower than that of the controls. Feed consumption by exposed males was similar to that by controls, and there were no clinical findings attributed to TBBC administration. Hematology and Clinical Chemistry: Hematocrit level, hemoglobin concentration, and erythrocyte count in 1,000 ppm male mice were significantly lower than those in controls at the 15-month interim evaluation. Serum alkaline phosphatase activities in 1,000 ppm males were slightly but significantly greater than those in controls at 3 and 9 months, as was the serum alkaline phosphatase activity in 1,000 ppm females at 9 months. Serum levels of total bilirubin in all exposed groups of males were significantly greater than those in controls at 9 and 15 months. Pathology Findings: In the liver of male mice, negative trends in the incidences of fatty change, clear cell foci, and adenoma or carcinoma combined occurred at the end of the 2-year study. There were no compound-related increased incidences of neoplasms or nonneoplastic lesions in mice receiving TBBC for 2 years. A negative trend in the incidence of fatty change in the liver of male mice also occurred at 15 months. GENETIC TOXICOLOGY: 4,4'-Thiobis(6- t -butyl- m -cresol) was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Sister chromatid exchanges were induced in cultured Chinese hamster ovary cells treated with TBBC, with and without S9, but no increases in chromosomal aberrations were noted in cultured Chinese hamster ovary cells after treatment with TBBC. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of 4,4'-thiobis(6- t -butyl- m -cresol) in male or female F344/N rats administered 500, 1,000, or 2,500 ppm or in male or female B6C3F1, mice administered 250, 500, or 1,000 ppm. Nonneoplastic lesions associated with exposure to TBBC included: Kupffer cell hypertrophy, cytoplasmic vacuolization, and mixed cell foci in the liver of male and female rats, fatty change in the liver of female, rats, and an increase in the severity of nephropathy in the kidney of female rats. In addition, decreased incidences of fibroadenoma, adenoma, or carcinoma (combined) were observed in the mammary gland of female rats. Decreases also occurred in the incidences of fatty change, clear cell foci, and adenoma or carcinoma (combined) in the liver of male mice. Synonyms: 4,4'-Thiobis(6- t -butyl-3-cresol); bis(3- t -butyl-4-hydroxy-6-methylphenyl)sulfide
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PMID:NTP Toxicology and Carcinogenesis Studies of 4,4'-Thiobis(6- t -butyl- m -cresol) (CAS No. 96-69-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 28

Some pituitary adenomas seem to be related to bone loss. It is unknown what kinds of pituitary adenomas affect bone mass. We attempted to determine what kinds of pituitary adenomas caused osteoporosis, and whether hormonal disturbance in pituitary adenoma patients affected bone mass. This study included 53 surgical patients (39 women of premenopausal age and 14 men) aged 21 to 62 years. We measured vertebral bone mineral density (BMD); various bone metabolic parameters, such as serum calcium, phosphorus, alkaline phosphatase, and blood urea nitrogen, parathormone, vitamin D, vitamin K, and hormonal activity in the anterior lobe of the pituitary gland. Comparisons were made of the mean Z scores (the ratio to the mean BMD of age-matched healthy Japanese women and men) among patient groups and controls. Compared with the female controls, the mean Z score was significantly higher in the women with acromegalic adenoma and significantly lower in those with adrenocorticotrophic hormone (ACTH)-secreting adenoma. In male patients, the mean Z scores were significantly decreased in prolactin-secreting adenoma and nonfunctioning adenoma, compared with that in normal controls. Acromegalic adenoma contributes significantly to vertebral bone mass acquisition, although ACTH adenoma may carry a significant risk of osteoporosis in female patients. Male patients with prolactin-secreting and nonfunctioning adenoma have a significant risk of bone decrease.
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PMID:Various risks of osteoporosis in patients with pituitary adenomas. 1260 73

3,4-Dihydrocoumarin was nominated by the Food and Drug Administration and the National Cancer Institute for study because of its widespread use as a flavoring agent in beverages, gelatins, puddings, candy, and other food items; as a fragrance in perfumes, creams, and cosmetics; and because of interest in the structure-activity relationships of the coumarin derivatives. Toxicity and carcinogenicity studies were conducted by administering 3,4-dihydrocoumarin (99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood cells of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 190, 375, 750, 1,500, or 3,000 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All male and female rats given 3,000 mg/kg, and four male rats and five female rats given 1,500 mg/kg died. Body weight gains and final mean body weights of rats receiving 190, 375, or 750 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 16-DAY STUDY IN MICE: Groups of five male and five female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 140, 280, 560, 1,125, or 2,250 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All mice given 2,250 mg/kg died. Body weight gains and final mean body weights of mice receiving 140, 280, 560, and 1,125 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 75, 150, 300, 600, or 1,200 mg/kg body weight 5 days per week for 13 weeks. Two male rats and five female rats given 1,200 mg/kg died. The body weight gain and final mean body weight of male rats that received 1,200 mg/kg were significantly lower than those of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to or slightly greater than those of the controls. Platelet counts were significantly lower in males and females receiving 600 and 1,200 mg/kg and in females receiving 300 mg/kg. Hemoglobin and hematocrit values and erythrocyte counts were significantly lower in males that received 300 mg/kg or more. The absolute and relative liver and kidney weights of males and females receiving 600 and 1,200 mg/kg were significantly greater than those of the controls. Hepatocellular hypertrophy was observed in rats given 300, 600, and 1,200 mg/kg. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 100, 200, 400, 800, or 1,600 mg/kg body weight 5 days per week for 13 weeks. Eight male and five female mice receiving 1,600 mg/kg died. Deaths in other groups were attributed to dosing accidents. Final mean body weights of dosed male and female mice were similar to those of the controls, and there were no treatment-related changes in any hematologic parameters. The absolute and relative liver weights of males and females that received 1,600 mg/kg and the relative kidney weight of males that received 1,600 mg/kg were significantly greater than those of the controls. No treatment-related lesions were noted. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 3,4-dihydrocoumarin in corn oil by gavage at age at doses of 0, 150, 300, or 600 mg/kg body weight. After 15 months, up to 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival rates of dosed male rats were lower than that of the controls (O mg/kg, 28/51; 150 mg/kg, 12/50; 300 mg/kg, 8/50; 600 mg/kg, 2/50) but survival rates of dosed female rats were similar to that of the controls (31/50, 21/51, 26/50, 23/51). The decreased survival in dosed male rats was attributed to a chemical-related increase in the severity of nephropathy. The final mean body weight of male rats receiving 600 mg/kg was lower than that of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to those of the controls. No clinical findings related to chemical administration were observed. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the hemoglobin concentrations, mean erythrocyte volumes, or mean erythrocyte hemoglobin concentrations in the 300 and 600 mg/kg female rats were slightly, but significantly, lower than those of the controls. In males, only the hemoglobin concentration in the 600 mg/kg group was significantly lower. Serum levels of alkaline phosphatase, alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in the 300 and 600 mg/kg male rats were significantly higher than those in the controls. In females, alkaline phosphatase and g-glutamyltransferase levels were significantly higher in the 600 mg/kg group. Pathology Findings: The principal lesions associated with the administration of 3,4-dihydrocoumarin to rats occurred in the kidney and forestomach. There was a chemical related increase in the severity of nephropathy in all dosed male rats and in 300 and 600 mg/kg female rats. There was a corresponding increased incidence of parathyroid gland hyperplasia, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, renal tubule adenomas were observed in one 150 and two 600 mg/kg males and one each in the control, 150, and 300 mg/kg females. Transitional cell carcinomas were also observed in two 600 mg/kg male rats. However, an extended evaluation of step sections identified significantly higher incidences of focal hyperplasia and adenoma in the 600 mg/kg males than in controls (hyperplasia: 0/50, 5/48, 6/47, 8/50; adenoma: 1/50,1/48, 3/47, 6/50). The incidence of forestomach ulcers in all groups of dosed male rats was significantly greater than that of the controls (4/47, 14/48, 20/50, 16/46). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle until they died or until the end of the study. Similarly, a group of 30 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil until the end of the study. A group of 20 vehicle control male rats was necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. The severity of nephropathy in male rats of the stop-exposure groups was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This was expected because nephropathy is a progressive degenerative disease that naturally increases in severity with age. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 200, 400, or 800 mg/kg body weight. After 15 months, five to 10 animals from each group were evaluated. Additional groups of 8 to 10 animals were evaluated for clinical pathology after 15 months. Survival, Body Weights, and Clinical Findings Survival rates of dosed male and female mice were similar to those of the controls (males: O mg/kg, 42/50; 200 mg/kg, 39/51; 400 mg/kg, 34/51; 800 mg/kg, 38/50; females: 36/51, 39/50, 41/50, 28/52). Final mean body weights of dosed male and female mice were similar to those of the controls. No clinical findings were noted that were related to chemical administration. Hematology and Clinical Chemistry: There were no differences in hematology or clinical chemistry parameters that were considered to be chemical related. Pathology Findings: The principal neoplasms associated with the administration of 3,4-dihydrocoumarin to mice occurred in the liver. There were significantly increased incidences of hepatocellular adenomas in all groups of dosed female mice. Further, the incidences of multiple hepatocellular adenomas in dosed female mice were greater than that of the controls (control, 0/51; 200 mg/kg, 6/50; 400 mg/kg, 9/50; 800 mg/kg, 9/52). However, there was no corresponding increased incidence of hepatocellular carcinoma in dosed female mice (3/51, 2/50, 4/50, 6/52), and the incidences of hepatocellular adenoma or carcinoma were similar between dosed and control male groups (adenoma: 29/50, 23/51, 36/51, 31/50; carcinoma: 11/50, 11/51, 11/51, 6/50). The incidence of alveolar/bronchiolar adenoma in the 200 and 400 mg/kg male mice was marginally greater than that of the controls (8/50,15/50,15/51,10/50). However, these neoplasms were not considered chemical related because the increased incidence was slight and there was no corresponding increased incidence in the 800 mg/kg group. The incidence of alveolar/bronchiolar neoplasms in female mice was similar between the dosed and control groups (adenoma: 2/51, 5/50, 1/48, 3/51; carcinoma: 0/51, 1/50, 0/48, 0/51). In the standard evaluation of single sections of kidney, focal hyperplasia and adenoma or carcinoma of the renal tubule were identified in several dosed male mice, but not in controls [adenoma or carcinoma (combined): 0/50,1/51, 2/51,1/49; hyperplasia: 2/50, 2/51, 5/51, 2/49]. In an extended evaluation of step sections, a few additional males with focal hyperplasia or renal tubule adenomas were identified in the dosed groups. However, the incidences of these lesions in dosed groups of male mice were not significantly greater than those of the controls, and did not increase with dose (hyperplasia: 0/50,1/51, 3/51, 1/49; renal tubule adenoma: 0/50, 0/51, 2/51, 1/49). Therefore, the low number of renal tubule neoplasms in male mice was not considered to be chemical related. GENETIC TOXICOLOGY: 3,4-Dihydrocoumarin did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No induction of micronuclei was noted in peripheral blood erythrocyte samples obtained from male and female B6C3F1 mice at the end of the 13-week toxicology study. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N rats based on increased incidences of renal tubule adenomas and focal hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also have been chemical related. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3F1 mice receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). 3,4-Dihydrocoumarin caused ulcers, hyperplasia, and inflammation of the forestomach, parathyroid gland hyperplasia, and increased severity of nephropathy in male rats. Synonyms: 1,2-benzodihydropyrone, 2H-1-benzopyran-2-one, 2-chromanone, 3,4-dihydro-2H-1-benzopyran-2-one, dihydrocoumarin, hydrocoumarin, o-hydroycinnamic acid, delta-lactone-hydrocinnamic acid, melilotin, melilotine, melilotol, 2-oxochroman
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin (CAS No. 119-84-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 88

Talc ore may contain several other minerals including calcite, dolomite, magnesite, tremolite, anthophyllite, antigorite, quartz, pyrophyllite, micas, or chlorites. Talc products are sold in a multitude of grades which have physical or functional characteristics especially suited for particular applications, so occupational and consumer exposures to talc are complex. Epidemiology studies have suggested an association between non-fibrous talc and lung cancer risk. Talc was nominated by the National Institute of Occupational Safety and Health (NIOSH) for study by the NTP because of widespread human exposure and because of the lack of adequate information on its chronic toxicity and potential carcinogenicity. Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade), a finely powdered hydrous magnesium silicate, were conducted by exposing groups of F344/N rats to aerosols for 6 hours per day, 5 days per week for up to 113 weeks (males) or 122 weeks (females). Groups of B6C3F1 mice were exposed similarly for up to 104 weeks. LIFETIME STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/m(3) talc until mortality in any exposure group reached 80% (113 weeks for males and 122 weeks for females). These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in F344/N rats; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provided a dose equivalent of 0, 2.8, or 8.4 mg/kg per day for male rats and 0, 3.2, or 9.6 mg/kg per day for female rats. In a special study, additional groups of 22 male and 22 female rats were similarly exposed and examined for interim pathology evaluations or pulmonary function tests after 6, 11, 18, and 24 months and lung biochemistry and cytology studies after 24 months. The talc aerosols had a median mass aerodynamic diameter of 2.7 mm in the 6 mg/m(3) chamber and a median diameter of 3.2 mm in the 18 mg/m(3) chamber, with geometric standard deviations of 1.9 mm. However, there was a 7-week period beginning at study week 11 during which the chamber concentration for the 18 mg/m(3) rats varied from approximately 30 to 40 mg/m(3) because of difficulties with the aerosol concentration monitoring system. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: The survival of male and female rats exposed to talc was similar to that of the controls. Mean body weights of rats exposed to 18 mg/m(3) were slightly lower than those of controls after week 65. No clinical findings were attributed to talc exposure. Pathology Findings: Absolute and relative lung weights of male rats exposed to 18 mg/m(3) were significantly greater than those of controls at the 6-, 11-, and 18-month interim evaluations and at the end of the lifetime study, while those of female rats exposed to 18 mg/m(3) were significantly greater at the 11-, 18-, and 24-month interim evaluations and at the end of the lifetime study. Inhalation exposure of rats to talc produced a spectrum of inflammatory, reparative, and proliferative processes in the lungs. Granulomatous inflammation occurred in nearly all exposed rats and the severity increased with exposure duration and concentration. Hyperplasia of the alveolar epithelium and interstitial fibrosis occurred in or near foci of inflammation in many exposed rats, while squamous metaplasia of the alveolar epithelium and squamous cysts were also occasionally seen. Accumulations of macrophages (histiocytes), most containing talc particles, were found in the peribronchial lymphoid tissue of the lung and in the bronchial and mediastinal Iymph nodes. In female rats, the incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) in the 18 mg/m(8 mg/m(3) group were significantly greater than those of controls. The incidences of pulmonary neoplasms in exposed male rats were similar to those in controls. Minor alterations attributed to talc exposure were also observed in the upper respiratory tract. Hyperplasia of the respiratory epithelium of the nasal mucosa in males and accumulation of cytoplasmic, eosinophilic droplets in the nasal mucosal epithelium in male and female rats occurred with a concentration-related increased incidence in the exposed groups. Adrenal medulla pheochromocytomas [benign, malignant, or complex (combined)] occurred with a significant positive trend in male and female rats, and the incidences in the 18 mg/m(3) groups were significantly greater than those of controls. Although adrenal medulla hyperplasia occurred with similar frequency among exposed and control females, the incidences of hyperplasia in exposed males were significantly lower than in controls. Lung Talc Burden: Lung talc burdens of male and female rats exposed to 6 mg/m(3) were similar and increased progressively from 6 to 24 months. Lung talc burdens of females exposed to 18 mg/m(3) also increased progressively from 6 to 24 months, while those of males exposed to 18 mg/m(3) remained about the same after 18 months. Lung burdens were generally proportional to exposure concentration at each interim evaluation. Pulmonary Function, Bronchoalveolar Lavage, and Lung Biochemistry: In exposed male and female rats there was a concentration-related impairment of respiratory function which increased in severity with increasing exposure duration. The impairment was characterized by reductions in lung volume (total lung capacity, vital capacity, and forced vital capacity), lung compliance, gas exchange efficiency (carbon monoxide diffusing capacity), and nonuniform intrapulmonary gas distribution. After 24 months, males exposed to 6 mg/m(3) talc had a significant increase in beta-glucuronidase and polymorphonuclear leukocytes; males exposed 18 mg/m(3) had significant increases in b -glucuronidase, lactate dehydrogenase, alkaline phosphatase, and total protein in bronchoalveolar lavage fluid. All exposed females had significantly increased a-glucuronidase, lactate dehydrogenase, alkaline phosphatase, total protein, and polymorphonuclear leukocytes; 18 mg/m(3) females also had significantly increased glutathione reductase. Viability and phagocytic activity of macrophages recovered from lavage fluid were not affected by talc exposure. Total lung collagen was significantly increased in rats at both exposure concentrations after 24 months, while collagenous peptides in lavage fluid and the percentages of newly synthesized protein from females, but not males, were also significantly increased at the 6 or 18 mg/m(3) levels. In addition, lung proteinase activity, primarily cathepsin D-like activity, was significantly greater in exposed males and females. Rats exposed to talc also had significant increases in collagenous peptides and acid proteinase in lung homogenates. 2-YEAR STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to aerosols containing 0, 6, or 18 mg/m(3) talc for up to 104 weeks. These exposures were selected based on 4-week inhalation studies of the terminal lung talc burden in B6C3F1 mice; concentrations greater than 18 mg/m(3) were expected to overwhelm lung clearance mechanisms and impair lung function. These exposure concentrations provide a dose equivalent of 0, 2, or 6 mg/kg per day for male mice and 0, 1.3, or 3.9 mg/kg per day for female mice. In a special study, additional groups of 39 or 40 male and 39 or 40 female mice similarly exposed were examined for interim pathology evaluations, lung biochemistry, and cytology studies after 6, 12, and 18 months of exposure. The talc aerosols had a median mass aerodynamic diameter of 3.3 mm with a geometric standard deviation of 1.9 mm in the 6 mg/m(3) chamber, and a median diameter of 3.6 mm with a geometric standard deviation of 2.0 mm in the 18 mg/m(3) chamber. Further, there was a 12-week period beginning at approximately week 70 during which there were difficulties in generating the talc aerosol, and the chamber concentrations for rats and mice were substantially lower than the target concentrations. Survival, Body Weights, and Clinical Findings: Survival and final mean body weights of male and female mice exposed to talc were similar to those of the controls. There were no clinical findings attributed to talc exposure. Pathology Findings: Inhalation exposure of mice to talc was associated with chronic active inflammation and the accumulation of macrophages in the lung. In contrast to rats, hyperplasia of the alveolar epithelium, squamous metaplasia, or interstitial fibrosis were not associated with the inflammatory response in mice, and the incidences of pulmonary neoplasms in exposed and control groups of mice were similar. Accumulations of macrophages (histiocytes) containing talc particles were also present in the bronchial Iymph node. In the upper respiratory tract, cytoplasmic alteration, consisting of the accumulation of cytoplasmic eosinophilic droplets in the nasal mucosal epithelium, occurred with a concentration-related increased incidence in exposed male and female mice. Lung Talc Burden: Lung talc burdens of mice exposed to 6 mg/m(3) were similar between males and females and increased progressively from 6 to 24 months, except for males at 18 months. The lung talc burdens of mice exposed to 18 mg/m(3) were also similar between the sexes at each interim evaluation. Although the talc burdens of males and females increased substantially from 6 to 24 months, the values at 12 and 18 months were similar. Generally, lung burdens of mice exposed to 18 mg/m(3) were disproportionately greater than those of mice exposed to 6 mg/m(3), suggesting that clearance of talc from the lung was impaired, or impaired to a greater extent, in mice exposed to 18 mg/m(3) than in mice exposed to 6 mg/m(3). Bronchoalveolar Lavage and Lung Biochemistry: Increases in total protein, beta-glucuronidase, lactate dehydrogenase, glutathione reductase, total nucleated cells, and polymorphonuclear leukocytes in bronchoalveolar lavage fluid were observed primarily in mice exposed to 18 mg/m(3), although some parameters were also increased in mice exposed to 6 mg/m(3). The amount of collagenous peptides in lavage fluid and total lung collagen were increased in male and female mice exposed to 18 mg/m(3). Acid proteinase activity, principally cathepsin D-like activity, of lung homogenate supernatant fluid was also significantly increased in mice at the 18 mg/m(3) exposure concentration. CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/m(3). The principal toxic lesions associated with inhalation exposure to the same concentrations of talc in rats included chronic granulomatous inflammation, alveolar epithelial hyperplasia, squamous metaplasia and squamous cysts, and interstitial fibrosis of the lung. These lesions were accompanied by impaired pulmonary function characterized primarily by reduced lung volumes, reduced dynamic and/or quasistatic lung compliance, reduced gas exchange efficiency, and nonuniform intrapulmonary gas distribution. In mice, inhalation exposure to talc produced chronic inflammation of the lung with the accumulation of alveolar macrophages. Synonyms: talcum; agalite; emtal 596; non-asbestiform talc; non-fibrous talc; steatite; hydrous magnesium silicate
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PMID:NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1261 90

Turmeric oleoresin is the organic extract of turmeric, a ground powder from the root of the Curcuma plant, and is added to food items as a spice and coloring agent. Turmeric oleoresin, turmeric, and curcumin (the major component found in turmeric) were nominated by the National Cancer Institute and the Food and Drug Administration for study because these chemicals are used in food items and curry powders, and there was little information on their toxic or carcinogenic properties. Pure curcumin was not available in sufficient quantities for study, and a turmeric oleoresin with a high curcumin content (79% to 85%) was selected for evaluation. Toxicity and carcinogenicity studies were conducted by administering turmeric oleoresin in feed to groups of male and female F344/N rats and B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 5,000, 10,000, 25,000, or 50,000 ppm turmeric oleoresin. All rats survived until the end of the study. The final mean body weight of males receiving 50,000 ppm was 5% lower than that of the controls. Feed consumption by exposed male and female rats was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 50, 250, 480, 1,300, or 2,600 mg/kg body weight to males and 60, 300, 550, 1,450, or 2,800 mg/kg to females. The absolute and relative liver weights of female rats and the relative liver weights of male rats receiving 5,000, 10,000, 25,000, and 50,000 ppm were significantly greater than those of the controls. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters. Clinical findings included stained fur, and discolored feces and urine of exposed animals, presumably due to the parent compound or its metabolites. Hyperplasia of the mucosal epithelium was observed in the cecum and colon of male and female rats that received 50,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0,1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin. There were no deaths attributed to turmeric oleoresin and the final mean body weight gains and final mean body weights of all exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 150, 750, 1,700, 3,850, or 7,700 mg/kg body weight to males and 200, 1,000, 1,800, 4,700 or 9,300 mg/kg to females. Absolute and relative liver weights of male mice that received 5,000 ppm and male and female mice that received 10,000, 25,000 and 50,000 ppm were significantly greater than those of the controls. Clinical findings in mice included stained fur, and discolored feces and urine. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters, and there were no chemical related histopathologic lesions. 2-YEAR STUDY IN RATS: The exposure level selection for the 2-year study was based on the 13-week study, which showed that rats could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female F344/N rats were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 104 (males) or 103 (females) weeks, which were estimated to deliver average daily doses of 80, 460, or 2,000 mg/kg to males and 90, 440, or 2,400 mg/kg to females. Nine or 10 rats from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female rats was similar to that of the controls (male: O ppm, 18/50; 2,000 ppm, 17/50; 10,000 ppm, 15/50; 50,000 ppm, 17/50; female: 33/50, 27/50, 28/50, 34/50). Th50, 28/50, 34/50). The final mean body weights of all exposed male rats and female rats receiving 2,000 and 10,000 ppm were similar to those of the controls. The final mean body weights of male and female rats that received 50,000 ppm were slightly lower (up to 10%) than those of the controls throughout much of the study. Feed consumption by exposed male and female rats was similar to that by controls throughout the study. The absolute and relative liver weights of female rats receiving 10,000 or 50,000 ppm were significantly greater than those of controls at the 15-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: In male and female rats receiving 50,000 ppm the hematocrit values, hemoglobin concentrations, and erythrocyte counts at the 15-month interim evaluation were significantly lower than those in the controls. In addition, platelet counts in male and female rats that received 50,000 ppm and reticulocyte counts in male rats that received 50,000 ppm were significantly higher than those in the controls. No biologically significant differences were observed in clinical chemistry parameters. Pathology Findings: Chemical-related nonneoplastic lesions occurred in the gastrointestinal tract of rats that received 50,000 ppm. Males receiving 50,000 ppm had increased incidences of ulcers, hyperplasia, and hyperkeratosis of the forestomach. Male and female rats that received 50,000 ppm had ulcers, chronic active inflammation, and hyperplasia of the cecum. Similar lesions also occurred in the colon of males receiving 50,000 ppm. Male and female rats that received 50,000 ppm and male rats that received 10,000 ppm had significantly increased incidences of sinus ectasia of the mesenteric Iymph node. The incidences of clitoral gland adenoma in all exposed groups of female rats were significantly increased. Clitoral gland carcinomas occurred in one control female and in four 2,000 ppm females, but not in females that received 10,000 or 50,000 ppm. The incidences of clitoral gland adenoma or carcinoma (combined) in all exposed groups of female rats were similar (6/50, 16/48, 15/47, 16/49) and did not increase with exposure level. The incidence of clitoral gland hyperplasia was similar among exposed and control groups of female rats (7/50, 5/48, 4/47, 7149). 2-YEAR STUDY IN MICE: The exposure level selection for the 2-year study was based on the 13-week study, which showed that mice could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 103 weeks, which were estimated to deliver average daily doses of 220, 520, or 6,000 mg/kg to males and 320,1,620, or 8,400 mg/kg to females. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls (male: O ppm, 43/50; 2,000 ppm, 43/50; 10,000 ppm, 37/50; 50,000 ppm 42/50; female: 39/50, 41/50, 34/50, 42/50). The mean body weight of female mice receiving 50,000 ppm was slightly lower (up to 12%) than that of the controls from about week 25. The final mean body weights of males that received 50,000 ppm and females that received 10,000 and 50,000 ppm were significantly lower than those of controls. The final mean body weights of other exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls throughout the study. The absolute and relative liver weights of male and female mice receiving 10,000 and 50,000 ppm were significantly greater than those of the controls at the l5-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: No biologically significant differences were observed in hematologic parameters. The alkaline phosphatase values of male and female mice that received 10,000 and 50,000 ppm were significantly higher than those of controls at the 15-month interim evaluation. Pathology Findings: The incidences of hepatocellular adenoma in male and female mice receiving 10,000 ppm, but not those in mice receiving 2,000 or 50,000 ppm, were significantly increased (male: 25/50, 28/50, 35/50, 30/50; female: 7/50, 8/50, 19/51, 14/50). The number of male and female mice in the 10,000 and 50,000 ppm groups with multiple hepatocellular neoplasms was significantly greater than that in the controls. The incidences of hepatocellular carcinoma were similar among exposed and control groups. In contrast to rats, there were no chemical-related nonneoplastic lesions of the gastrointestinal tract in mice. Three males that received 2,000 ppm and three males that received 10,000 ppm had carcinomas of the small intestine; neoplasms of the small intestine were not observed in control males or in males that received 50,000 ppm. Female mice receiving 50,000 ppm had a significantly increased incidence of thyroid gland follicular cell hyperplasia. GENETIC TOXICOLOGY: Turmeric oleoresin was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9). It induced small but significant increases in sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. The positive response in the sister chromatid exchange test occurred in the presence of S9, whereas the aberrations response occurred without S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of turmeric oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female F344/N rats based on increased incidences of clitoral gland adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice based on an increased incidence of hepatocellular adenomas in the 10,000 ppm group. Turmeric oleoresin ingestion was also associated with increased incidences of ulcers, hyperplasia, and inflammation of the forestomach, cecum, and colon in male rats and of the cecum in female rats. In female mice, ingestion of diets containing turmeric oleoresin was also associated with an increased incidence of thyroid gland follicular cell hyperplasia. Synonyms for Turmeric Oleoresin: curcuma oil; oil of turmeric; turmeric oil; curcuma longa oils; curcuma long oil; Curcumin Synonyms for Curcumin: 1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; C.I. Natural Yellow 3; C.I. 75300; Curcuma; diferuloylmethane; E 100; Haidr; Halad; Haldar; Halud; HSDB 4334; Indian Saffron; kacha haldi; Kurkumin; merita earth; Souchet; Turmeric Yellow; yellow ginger; yellow root; Yo-kin; Zlut Prirodni 3; NCI-C613253
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PMID:NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 4

The purpose of this study was to evaluate the incidence and severity of hypocalcemia after parathyroidectomy and delineate its risk factors. Data was retrieved from a prospective database. Patients with postoperative hypocalcemia were identified and risk factors were investigated including primary versus renal hyperparathyroidism (HPT), preoperative calcium, parathyroid hormone (PTH) and alkaline phosphatase levels, gland weight, pathology, extent of surgery, and reoperative surgery. Of the 162 patients who underwent parathyroidectomy, 84 (52%) were hypocalcemic postoperatively: 55 (42%) of 132 patients with primary and 29 (97%) of 30 patients with renal HPT (P = 0.0001). Patients with renal HPT had more profound hypocalcemia with a mean +/- SD calcium of 7.34 mg/dL +/- 1.07 versus 7.76 mg/dL +/- 0.59 for patients with primary HPT (P < 0.05). Symptoms were present in 28 (51%) of 55 patients with primary and 13 (45%) of 29 patients with renal HPT. Only three (2%) patients with primary compared to 29 (97%) with renal HPT were treated with intravenous calcium. The average length of stay for hypocalcemic patients was 0.7 days for primary HPT versus 4.7 days for renal HPT (P < 0.0005). Patients with primary HPT who underwent subtotal parathyroidectomy had significantly lower postoperative calcium levels (7.95 mg/dL +/- 0.64) than patients who had a single or double adenoma removed (8.49 mg/dL +/- 0.79) (P = 0.036). No other factor was predictive of postoperative hypocalcemia. Patients with renal HPT develop profound postoperative hypocalcemia requiring intravenous calcium and vitamin D therapy. Hypocalcemia in patients with primary HPT develop less severe hypocalcemia that is amenable to outpatient oral calcium therapy and should be routinely initiated following subtotal parathyroidectomy.
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PMID:Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management. 1501 12

This is a review of ectopic localizations of the parathyroid gland in one case. A hard mobile mass (2 x 2.5 cm) was detected on the right side of the neck of a patient who had previously been given a diagnosis of hyperparathyroidism. Computed tomography showed an adenoma (25 x 35 mm) in the paratracheal region on the right side of the neck. Scintigraphy revealed an activity increase on the right side of the neck and in the left axillary region. Blood measurements were as follows: Ca, 12.7 mEq/l; parathyroid hormone (PTH), 235 U/l; and alkaline phosphatase (ALP), 776 U/l. The patient was operated on to remove the lesions located in the cervical and left axillary regions. Histopathological examination revealed that the lesion in the right cervical region was a parathyroid adenoma, whereas the lesion in the left axillary region was normal parathyroid gland tissue. Parathyroid glands may indicate ectopic locations in very different regions. We think the case presented here is the first case with this axillary location. Scintigraphy, alone or combined with other methods, may be used to determine ectopic localizations.
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PMID:An ectopic parathyroid gland in the left axillary region: case report. 1508 90

We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 x 2.8 x 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.
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PMID:A rare case of primary hyperparathyroidism with clear cell adenoma. 1511 72


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