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

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

C-reactive protein (CRP) is the main acute phase reactant in humans. Its production is presumably restricted to the liver but extrahepatic expression by inflamed tissue has not been studied in detail. By real-time PCR and immunohistochemistry we here show that renal cortical tubular epithelial cells (TEC) express CRP mRNA and protein within 6 h after stimulation with conditioned medium (CM) or IL-6, but not IL-1alpha or TNF-alpha. Western blot analysis with monoclonal anti-CRP antibody that recognizes native CRP revealed protein secretion into supernatants of CM-stimulated TEC cultures. While hepatoma-derived Hep3B cells could be induced similarly, peripheral blood mononuclear cells could not. CRP mRNA transcripts were observed in nephrectomized renal allografts with severe acute rejection but not with chronic allograft nephropathy (CAN). Of 19 needle biopsies of acutely rejecting kidney transplants, 15 demonstrated CRP mRNA production with the relative expression levels increasing with the severity of rejection. On the other hand, none of 7 graft biopsies with acute tubular necrosis (ATN) or CAN showed CRP mRNA expression. By using monoclonal anti-CRP antibody, cortical tubules as well as glomerular cells were shown to locally express CRP in rejecting, but not in ATN kidneys. We conclude that inflamed kidneys represent a so far unknown site of CRP formation in vivo. These data shed new light on the acute phase reaction not merely representing a systemic inflammatory pathway but probably being part of the local immune response.
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PMID:The kidney as a second site of human C-reactive protein formation in vivo. 1259 44

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

Triamterene is a potassium-sparing diuretic used in the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and other diseases in which edema may occur. Toxicity and carcinogenicity studies were conducted by administering triamterene (greater than 99% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 15 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 15-day Studies: Groups of five male and five female rats were fed diets containing 0, 1,000, 3,000, 10,000, 30,000, or 60,000 ppm triamterene. The diets containing 10,000 ppm or more were unpalatable, and feed consumption by the 3,000 ppm groups was reduced. Rats exposed to 1,000 or 3,000 ppm triamterene received approximate doses of 80 or 60 mg/kg body weight per day (males) or 70 or 50 mg/kg per day (females). One male rat and two female rats receiving 3,000 ppm died during the second week of the study. The final mean body weights of 3,000 ppm male and female rats were significantly lower than those of controls. Rats in the 3,000 ppm groups had renal tubule regeneration and cytoplasmic vacuolization of the zona glomerulosa of the adrenal gland. Groups of five male and five female mice were fed diets containing 0, 300, 1,000, 3,000, 10,000, or 30,000 ppm triamterene, but the diets containing 10,000 or 30,000 ppm were unpalatable. All mice receiving 3,000 ppm died by day 6. Mice exposed to 300 or 1,000 ppm triamterene received approximate doses of 40 or 155 mg/kg body weight per day (males) or 45 or 170 mg/kg body weight per day (females). The final mean body weights of mice in the 300 and 1,000 ppm groups were similar to those of the controls. Renal tubule degeneration and necrosis were observed in the kidney of 3,000 ppm mice. 13-Week Studies: Groups of 10 male and 10 female rats were fed diets containing 0, 150, 300, 600, 1,200, or 2,400 ppm triamterene. All rats receiving 2,400 ppm died before the end of the study; all other rats survived to the end of the study. Rats exposed to 150, 300, 600, or 1,200 ppm triamterene received approximate doses of 10, 20, 40, or 70 mg/kg body weight per day (males) or 10, 20, 40, or 80 mg/kg per day (females). Body weight gains and final mean body weights of rats in the 1,200 ppm groups were significantly lower than those of controls. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters among exposed and control rats. Calculi were observed in the renal pelvis of four male rats in the 1,200 ppm group. Chemical-related lesions were observed in the kidney and adrenal gland of rats in the 1,200 and 2,400 ppm groups. These consisted of degeneration and regeneration of the renal tubule epithelium and cytoplasmic vacuolization of cells of the zona glomerulosa of the adrenal cortex. Depletion of hematopoietic cells from the bone marrow and of lymphocytes from the spleen and thymus of rats in the 2,400 ppm groups may have been related to debilitation and reduced feed consumption rather than chemical exposure. Groups of 10 male and 10 female mice were fed diets containing 0, 100, 200, 400, 800, or 1,600 ppm triamterene. All mice receiving 1,600 ppm, one 800 ppm female, one 200 ppm male, and four 100 ppm males died before the end of the study. Mice exposed to 100, 200, 400, or 800 ppm triamterene received approximate doses of 15, 25, 50, or 90 mg/kg body weight per day (males) or 15, 25, 50, or 115 mg/kg per day (females). The body weight gain and final mean body weight of male mice receiving 800 ppm were significantly lower than those of the controls. The total leukocyte and lymphocyte counts of males receiving 800 ppm and of females receiving 100, 400, or 800 ppm were significantly lower than those of controls. No other differences in hematologic, clinical chemistry, or urinalysis parameters were considered to be biologically significant. Necrosis of Lymphocytes was observed in the lymph node, spleen, and thymus of mice in the 800 and 1,600 ppm groups groups. 2-Year Studies: The doses selected for the 2-year studies were based on lower body weights, mortality, and chemical-related lesions observed in exposed animals during the 13-week studies. Groups of 70 male and 70 female rats were fed diets containing 0, 150, 300, or 600 ppm triamterene and groups of 70 male and 70 female mice were fed diets containing 0, 100, 200, or 400 ppm. Ten animals from each group were included for interim evaluations at 3 and 15 months. Because of a dosing error involving the high-dose mice at week 40, a second study was conducted with groups of 60 male and 60 female mice fed diets containing 0 or 400 ppm triamterene. In the 2-year studies, rats exposed to 150, 300, or 600 ppm triamterene received approximately 5,10, or 25 mg/kg body weight per day (males) and 5, 15, or 30 mg/kg (females) and mice exposed to 100, 200, or 400 ppm received approximately 10, 25, or 45 mg/kg (males) and 15, 30, or 60 mg/kg (females) per day. 3-Month and 15-Month Interim Evaluations in the 2-Year Studies: There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters between exposed and control rats or mice at the 3- or 15-month interim evaluations. At necropsy, the mean body weights of exposed rats and mice were similar to those of the controls. There were no chemical-related lesions in exposed rats at 3 months or in exposed mice at 3 or 15 months. At the 15-month evaluation, basophilic, clear cell, and mixed cell foci of the liver occurred in exposed male rats. No chemical-related lesions were observed in female rats at 15 months. Survival, Body Weights, Clinical Findings, and Feed Consumption in the 2-Year Studies: Survival of exposed rats was similar to that of controls (males: 0 ppm, 25/47; 150 ppm, 25/50; 300 ppm, 19/50; 600 ppm, 27/50; females: 29/50, 34/50, 34/50, 29/50). The mean body weights of 600 ppm rats were consistently lower than, but within 5% of, those of controls after week 49. Feed consumption by male and female rats was similar among exposed and control groups throughout the studies. There were no clinical findings of toxicity. Survival of 400 ppm male mice in the first study was lower than that of controls because of the dosing accident at week 40. Survival of 100 and 200 ppm male mice and of all exposed groups of female mice in the first study and of exposed males and females in the second study was similar to controls (males: first study, 0 ppm, 47/50; 100 ppm, 45/50; 200 ppm, 46/50; 400 ppm, 46/60; second study, 0 ppm, 43/50; 400 ppm, 39/50; females: first study, 38/50; 43/50; 43/50; 43/60; second study, 40/50; 38/51). Mean body weights of exposed mice were similar to those of controls throughout the first study with one exception; in the week following the dosing error, the mean body weight of 400 ppm males was 16% lower than that of controls. In the second study, mean body weights of 400 ppm mice were slightly lower than those of controls during the final 8 weeks. Feed consumption by exposed mice was similar to that by controls throughout the studies. There were no clinical findings of toxicity in exposed mice. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: The incidences of mixed cell foci and focal hyperplasia of the liver were significantly increased in 300 and 600 ppm male rats, and the incidences of clear cell and mixed cell foci were significantly increased in 300 and 600 ppm female rats. Hepatocellular adenomas occurred in all groups of exposed male rats, but none occurred in controls; the incidence of hepatocellular adenoma in the 150 ppm males was significantly higher than that of controls (O ppm, 0/50; 150 ppm, 6/50; 300 ppm, 4/50; 600 ppm, 3/49). Hepatocellular adenomas were observed in two 600 ppm female rats, but not in the lower exposure groups or in controls. No hepatocellular carcinomas were seen in exposed or control rats. The incidences of nephropathy in exposed rats were similar to those of controls, but the average severity of the lesion was marginally increased in male rats receiving 300 ppm and in female rats receiving 600 ppm (males: 47/50, 2.4; 49/50, 2.7; 50/50, 3.0; 49/50, 2.8; females: 38/50, 1.1; 45/50, 1.2; 45/50, 1.3; 45/50, 1.4). Although in the first study the incidences of hepatocellular adenoma in exposed male mice were similar to that of controls, the incidences of multiple adenomas were greater in the exposed groups, and the incidence of hepatocellular carcinoma in the 400 ppm group was marginally greater (hepatocellular adenoma: 0 ppm, 17/50; 100 ppm, 22/50; 200 ppm, 19/50; 400 ppm, 20/60; hepatocellular carcinoma: 5/50; 7/50; 3/50; 13/60). In the second study, the incidence of hepatocellular adenoma in the 400 ppm males was significantly higher than that of controls (hepatocellular adenoma: 0 ppm, 21/50; 400 ppm, 36/50; hepatocellular carcinoma: 9/50; 11/50). The incidences of hepatocellular adenoma in exposed female mice in the first and second studies were significantly greater than those of controls (hepatocellular adenoma, first study: 10/50; 22/50; 23/50; 36/60; second study: 7/50; 28/51). The incidences of multiple adenoma were also increased in the exposed groups. Although the incidences of hepatocellular carcinoma were similar among exposed and control female mice in the first study, the incidence of hepatocellular carcinoma in the 400 ppm females in the second study was marginally greater than that of controls (hepatocellular carcinoma, first study: 4/50; 4/50; 3/50; 8/60; second study: 5/50; 11/50). In both studies, hepatocellular foci (basophilic, eosinophilic, clear cell, or mixed cell) also occurred more frequently in exposed female mice than in controls. The incidences of thyroid gland follicular cell hyperplasia in the 200 and 400 ppm males and in all exposed groups of females were significantly greater than those of controls in the first study. These findings were confirmed in the second study (follicular cell hyperplasia: males, first study, 3/50, 8/50, 16/50, 20/60; second study, 0/50,16/50; females, first study, 4/49,17/49,18/50, 28/60; second study, 9/50, 32/51). The incidences of follicular cell neoplasms were similar among exposed and control mice in both studies. The incidences (28/50, 36/50, 43/50, 49/60) and average severity (0.56, 0.80, 1.00, 1.07) of nephropathy were marginally higher in exposed female mice than in controls in the first study. In the second study, the differences in incidence (15/50, 21/50) and severity (0.38, 0.55) were not as great. It is uncertain if these increases were related to the ingestion of triamterene. The incidences and severity of nephropathy were similar among exposed and control male mice in both studies. Genetic Toxicology: Triamterene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). It did not induce chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Positive results were obtained for induction of sister chromatid exchanges in Chinese hamster ovary cells with and without S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of triamterene in male F344/N rats based on a marginal increase in the incidence of hepatocellular adenoma. There was no evidence of carcinogenic activity of triamterene in female F344/N rats administered 150, 300, or 600 ppm. There was some evidence of carcinogenic activity of triamterene in male B6C3F1 mice based on a marginal increase in the incidence of hepatocellular carcinoma in the first study and a significantly increased incidence of hepatocellular adenoma in the second study. There was some evidence of carcinogenic activity of triamterene in female B6C3F1 mice based on significantly increased incidences of hepatocellular adenoma and of adenoma and carcinoma (combined). Exposure to triamterene was associated with an increased incidence of hepatocellular foci, primarily mixed cell type, and an increase in the severity of nephropathy in female rats. In mice, exposure to triamterene was associated with an increased incidence of hepatocellular foci in females and an increased incidence of thyroid gland follicular cell hyperplasia in males and females. Synonyms: 6-Phenyl-2,4,7-pteridinetnamine; 6-phenyl-2,4,7-triaminopteridine; 2,4,7-triamino-6-phenypteridine; ademin; pterofen; pterophane; NSC-77625; SKF 8542 Trade names: Dyrenium, Dyazide, Dyren, Dytac, Jatropur, Maxzide, Noridyl, Triteren, Teriam, Urocaudal
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PMID:NTP Toxicology and Carcinogenesis Studies of Triamterene (CAS No. 396-01-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 91

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

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% (40/40) and hepatocellular carcinoma occurred with an overall incidence of 15% (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

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85% of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97%, 92%, and 70% of the control values, respectively. Mean body weights of high- and mid-dose females were about 85% of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94%, 81%, and 74% of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies). 1263 69

4,4'-Methylenedianiline is used primarily as a chemical intermediate in the closed system production of isocyanates and polyisocyanates. These chemicals are used extensively in the manufacture of rigid polyurethane foams for thermal insulation and in the production of semiflexible polyurethane foams for automobile safety cushioning. The saturated isocyante of 4,4'-methylenedianiline [4,4'-methylene-bis(cyclohexylisocyanate)] is an intermediate in the production of light-stable, high-performance polyurethane coatings. 4,4'-Methylenedianiline is also a curing agent for epoxy resins and urethane elastomers, a dye intermediate, and a corrosion inhibitor. NTP Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the high dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower (P=0.006) than that in controls. Mean body weight was reduced in high dose female rats and in high dose male and female mice. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Compound-related nonneoplastic lesions of the thyroid in female rats included follicular cysts and hyperplasia. The incidence of thyroid follicular cell hyperplasia was elevated in high dose male and female mice. The incidences of thyroid neoplasms in the high dose groups were elevated compared with those of the control groups for both sexes of both species. Thyroid follicular cell carcinoma was increased in male rats (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%: P</=0.012). Follicular cell adenoma was increased in high dose female rats (0/47; 2/47, 4%; 17/48, 35%: P<0.001), in high dose male mice (0/47; 3/49, 6%; 16/49, 33%: P<0.001), and in high dose female mice (0/50; 1/47, 2%; 13/50, 26%: P<0.001) as compared with controls. In female rats, thyroid C-cell adenoma was also elevated in a dose-related manner (0/47; 3/47, 6%; 6/48, 13%, P</=0.029). Dose-related increases in nonneoplastic lesions were observed for male rats (nonspecific liver dilatation) and for male and female rats (fatty metamorphosis and focal cellular change). Liver degeneration was present in 80% of the low dose and 60% of the high dose male mice but was not found in the controls. Neoplastic nodules of the liver were observed at greater incidences (P</=0.002) for low and high dose male rats as compared with controls (control, 1/50, 2%; low dose, 12/50, 24%, P</=0.002; high dose 25/50, 50%, P<0.001). Hepatocellular adenoma was increased in a dose-related manner in dosed female mice (3/50, 6%; 9/50, 18%; 12/50, 24%, P<0.011). Hepatocellular carcinoma was observed in greater incidence in dosed male mice (10/49, 20%; 33/50, 66%, P<0.001; 29/50, 58%, P<0.001) and in high dose female mice (1/50, 2%; 6/50, 12%; 11/50, 22%, P=0.002). Male rats had a dose related increase in kidney mineralization. Nephropathy was increased in dosed mice of both sexes; renal papillary mineralization was greater in high dose male mice and female mice than in the controls. Other tumors that were elevated in dosed animals included adrenal pheochromocytomas in male mice (control, 2/48, 4%; low dose, 12/49, 24%, P</=0.006; high dose, 14/49, 29%; P</=0.001), alveolar/bronchiolar adenoma in female mice (1/50, 2%; 2/50, 4%; 6/49, 12%, P</=0.05) and malignant lymphomas in female mice (13/50,26%; 28/50, 56%, P=0.002; 29/50, 58%; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male (13/50,26&percnt;; 28/50, 56&percnt;, P=0.002; 29/50, 58&percnt;; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male rats (historical control 3/3,663), transitional-cell papillomas of the urinary bladder in female rats (historical control, 3/3,664, 0.08&percnt;; low dose, 2/50, 4&percnt;; high dose, 1/50, 2&percnt;) and granulosa cell tumors of the ovary in female rats (historical control, 11/3,642, 0.3&percnt;; low dose, 3/50, 6&percnt;; high dose, 2/50, 4&percnt;). Decreases in tumor incidences were observed for leukemia in male rats (control, 12/50, 24&percnt;; low dose, 6/50, 12&percnt;; high dose, 5/50, 10&percnt;, P=0.048) and alveolar or bronchiolar adenomas (combined) in male mice (12/49, 24&percnt;; 9/49, 18&percnt;; 3/49, 6&percnt;, P&le;0.011). Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly increased incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive
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PMID:NTP Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1275 Jul 45

A carcinogenesis bioassay of technical grade pentachloroethane (95.5% pure, with 4.2% hexachloroethane) was conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/ N rats at doses of 75 or 150 mg/ kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/ kg. (Pentachloroethane is a solvent that was used primarily as an intermediate in the manufacture of tetrachloroethylene.) Doses were administered for 103 weeks for rats and 41-103 weeks for mice. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Prechronic testing (single-dose and 14-day and 13-week repeated-dose studies) did not indicate target organ toxicity for pentachloroethane. The dosage levels for the 2-year study were selected on the basis of survival and body weight gains during the prechronic test phase. Survival of high-dose rats of each sex was significantly (P<0.05) less than that of the controls. Mean body weights of dosed male and female rats were lower than those of the corresponding controls during the second year of the study. Final mean body weights for rats were 4%-5% lower for male rats and 8%-12% lower for female rats when compared to controls. Chronic, diffuse inflammation of the kidney, distinguishable from nephropathy seen in aging F344/ N rats, was found in male rats in a significant (P<0.001) and dose-related incidence (control, 4/50, 8%; low-dose, 14/49, 29%; high-dose, 33/50, 66%). Mineralization of the renal papilla, considered to be secondary to chronic inflammation, was also observed at increased incidences in dosed male rats. Pentachloroethane administration did not cause any increased incidences of tumors in either male or female rats. [See Note Added Subsequent to Peer Review.] Statistically significant negative trends were detected for subcutaneous tissue fibromas among males and for pituitary adenomas in both sexes. Forty-two high-dose male mice died by week 41, and the 8 remaining animals in the group were killed at that time. Twenty-five male control mice were killed at week 44 to serve as controls for the high-dose males. Only 22/50 (44%) of the low-dose male mice survived to the end of the study. All high-dose female mice were dead by week 74, and only 9/50 (18%) low-dose females survived to the end of the study. Mean body weights of mice were lower than those of controls. The incidence of hepatocellular carcinoma was significantly elevated in all groups of dosed mice (male: 4/48, 8%; 26/44, 59%, P<0.001; 7/45,16%; female: 1/46, 2%; 28/42, 67%, P<0.001; 13/45, 29% P<0.001). Early mortalities in the high-dose male mice precluded an evaluation of their lifetime incidence of hepatocellular carcinoma. There was a significant increase in incidence over that observed among 25 controls killed at week 44 (0/25 versus 7/45, P<0.05). There was also a significant (P<0.001) dose-related increase in hepatocellular adenoma in female mice (2/46, 4%; 8/42, 19%; 19/45, 42%). Under the conditions of this bioassay, technical grade pentachloroethane containing 4.2% hexachloroethane (a known carcinogen in mice) was not carcinogenic in F344/N rats. The decreased survival of dosed rats might have reduced the sensitivity for a carcinogenic response in this species. Pentachloroethane was nephrotoxic to male rats. Technical grade pentachloroethane was carcinogenic for B6C3F1 mice, causing hepatocellular carcinomas in males and females, and adenomas in females. NOTE ADDED SUBSEQUENT TO PEER REVIEW: After the Peer Review Panel meeting in June 1981, the National Toxicology Program determined that the kidney (especially in male F344/N rats) was a target organ for the short-chain chlorinated aliphatic hydrocarbons. This awareness came from the nonneoplastic and neoplastic diagnoses made on related chemicals in this class. Alerted to this lead, the NTP re-examined the originally-prepared histology slides on the rat kidney from the pentachloroethane bioassay. During the re-reading, additional renato this lead, the NTP re-examined the originally-prepared histology slides on the rat kidney from the pentachloroethane bioassay. During the re-reading, additional renal tubular adenomas were discovered. Unfortunately, these slides were lost after they arrived at the Gulf South Research Institute laboratory; by necessity, a new set of slides was prepared. In the second set of slides, three additional renal tubular-cell adenomas were discovered: one in a low-dose male and two in high-dose males; none were found in treated females or in male and female vehicle controls. Thus, rare tubular-cell adenomas of the kidney occurred in male rats with a dose-related trend (P&lt;0.05), and the incidence in the high-dose group was suggestive (P&lt;0.06; 0/50, 1/49, 4/50). Additionally, one control and one low-dose male each had an adenocarcinoma and another low-dose male had a carcinoma of the kidney (not otherwise specified); combining tubular-cell tumors reduced the statistical differences (1/50, 2/49, 4/50). These tumors are uncommon in male vehicle controls in the bioassay program, occurring in 1/293 (0.3&percnt;) at this bioassay testing laboratory and in 4/998 (0.4&percnt;) in all NCI/ NTP bioassay testing laboratories. All tumors in these gavage controls were adenocarcinomas. The National Toxicology Program considers that these rare tubular-cell tumors of the kidney in male rats indicate a target organ and may have been associated with the administration of pentachloroethane. These additional tumor diagnoses were not presented to the Peer Review Panel. These are, however, the incidence rates recorded and analyzed statistically in this technical report (See Table 5, Table Al, and Table A3 in the full document). Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonyms: pentalin
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PMID:Carcinogenesis Studies of Pentachloroethane (CAS No. 76-01-7) in F344/N Rats and B6C3F1 Mice (Gavage Study). 1277 4

Trichloroethylene (TCE), a halogenated chemical, has been tested for carcinogenicity in the National Cancer Institute's Carcinogenesis Bioassay Program. Trichloroethylene has been used primarily as a solvent in industrial degreasing operations. Other uses have been as a solvent in dry cleaning and food processing, as an ingredient in printing inks, paints. etc., and as a general anesthetic or analgesic. Industrial grade (>99% pure) trichloroethylene was tested using 50 animals per group at 2 doses and with both sexes of Osborne-Mendel rats and B6C3F1 mice. Twenty of each sex and species were maintained as matched controls, in addition to colony and positive carcinogen controls. Animals were exposed to the compound by oral gavage 5 times per week for 78 weeks. At the end of treatment, animals were observed until terminal sacrifice at 110 weeks for rats and 90 weeks for mice. A complete necropsy and microscopic evaluation of all animals (except 7 of the original 480) was conducted. Two doses were used with animals started on test at approximately 6 weeks of age. The initial doses used in this test were the estimated maximum tolerated dose (MTD) and 1/2 MTD, as predicted from data obtained in a 6-week toxicity study. For rats, the initial doses were 1,300 and 650 mg/kg body weight. These were changed, based upon survival and body weight data, so that the "time-weighted average" doses were 549 and 1,097 mg/kg for both male and female rats. For mice, the initial doses were 1,000 and 2,000 mg/kg for males and 700 and 1,400 mg/kg for females. The doses were increased so that the "time-weighted average" doses were 1,169 and 2,339 mg/kg for male mice and 869 and 1,739 mg/kg for female mice. Clinical signs of toxicity, including reduction in weight, were evident in treated rats. These, along with an increased mortality rate necessitated a reduction in doses during the test. In contrast, very little evidence of toxicity was seen in mice, so doses were increased slightly during the study. The increased mortality in treated male mice appears related to the presence of liver tumors. A variety of neoplastic lesions were observed in rats with no significant difference between trichloroethylene-treated and control animals. The only lesion that might be attributed to the treatment was a chronic nephropathy found in both sexes and at both dose levels. With both male and female mice, primary malignant tumors of the liver, i.e., hepatocellular carcinoma, were observed in high numbers. For males, 26/50 low dose and 31/48 high dose animals had hepatocellular carcinomas as compared with 1/20 matched controls and 5/77 colony controls. The differences between treated and matched control males at both doses were highly significant (P<0.01). For females, hepatocellular carcinomas were observed in 4/50 low dose and 11/47 high dose animals as compared with 0/20 matched controls and 1/80 colony controls. While the difference between the high dose female mice and matched controls was also highly significant (P<0.01), the difference at the low dose was less (P=0.09). For both male and female mice, age-adjusted tests for linear trend (dose response) were highly significant for hepatocellular carcinoma (P<0.001 for males and P=0.002 for females). In male mice at the high doses, hepatocellular carcinomas were observed early in the study. The first was seen at 27 weeks; 9 others were found in male mice dying by the 78th week. The tumor was not observed so early in low dose male or female mice. The diagnosis of hepatocellular carcinoma was based on size, histologic appearance, and presence of metastasis, especially to the lung. No other lesion was significantly elevated (P<0.05) in treated mice. The incidence of hepatocellular carcinomas in the trichloroethylene-matched controls was typical of that observed in colony controls. Carbon tetrachloride (CCl4) was used as a positive control for the series of chlorinated chemicals which included trichloroethylene. While virtually all male and female mice developed hepatocellular carcinomas following carbon tetrachloride treatment, the response in the Osborne-Mendel rats was considerably less. Only about 5% developed hepatocellular carcinomas. Thus, there appears to be a marked difference in sensitivity to induction of carcinomas by chlorinated compounds between the B6C3F1 mouse and the Osborne-Mendel rat. The results of this carcinogenesis test of trichloroethylene clearly indicate that trichloroethylene induced a hepatocellular carcinoma response in mice. While the absence of a similar effect in rats appears most likely attributable to a difference in sensitivity between the Osborne-Mendel rat and the B6C3F1 mouse, the early mortality of rats due to toxicity must also be considered.
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PMID:Carcinogenesis bioassay of trichloroethylene. 1284 47

The bioassay of U.S.P.-grade tetrachloroethylene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Tetrachloroethylene in corn oil was administered by gavage at either of two dosages to groups of 50 male and 50 female animals of each species, 5 days a week, over a period of 78 weeks followed by an observation period of 32 weeks for rats and 12 weeks for mice. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The high and low time-weighted average dosages of tetrachloroethylene in the chronic study were 941 and 471 mg/kg/day for the male rats, 949 and 474 mg/kg/day for the female rats, 1,072 and 536 mg/kg/day for the male mice, and 772 and 386 mg/kg/day for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same time that dosed animals were gavaged with tetrachloroethylene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. No significant increased incidence of neoplastic lesions was observed in treated rats. In both dosed and control rats, respiratory disease was observed with increasing frequency for the latter part of the first year until termination of the bioassay. Lesions indicative of pneumonia were observed in nearly all rats at necropsy. A high incidence of toxic nephropathy was observed in treated rats. Toxic nephropathy was noted in rats that died early in the study (as early as week 20 for male rats and week 28 for female rats). Mortality of rats was dose-related. Fifty percent of the high dose males had died by week 44 and 50 percent of the high dose females had died by week 66. In both male and female mice, administration of tetrachloroethylene was associated with a significantly increased incidence of hepatocellular carcinoma. Hepatocellular carcinomas were observed in 2/17 (12 percent) untreated control males, 2/20 (10 percent) vehicle control males, 32/49 (65 percent) low dose males, 27/48 (56 percent) high dose males, 2/20 (10 percent) untreated control females, 0/20 vehicle control females, 19/48 (40 percent) low dose females, and 19/48 (40 percent) high dose females. Hepatocellular carcinomas metastasized to the kidney in one untreated control male and to the lung in three low dose males, one low dose female, and one high dose female. Toxic nephropathy, similar to that observed in rats, was also observed in treated but not control mice. Fisher exact tests indicated a highly significant increased incidence of hepatocellular carcinoma for each dosed group compared to each control group. Cochran-Armitage tests showed a highly significant positive association between increased dosage and elevated tumor incidence. Time-adjusted analyses, based on Kaplan and Meier survival curves, indicated that the estimated probability of observing hepatocellular carcinoma by week 91 was 1.00 in a dosed male mouse and 0.938 in a dosed female mouse. The results of the bioassay of tetrachloroethylene in Osborne-Mendel rats do not allow an evaluation of the carcinogenicity of this compound due to the high rate of early death among the treated animals. However, under the condition of this study, tetrachloroethylene is a liver carcinogen in B6C3F1 mice of both sexes.
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PMID:Bioassay of tetrachloroethylene for possible carcinogenicity. 1284 53


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