UMLS:C0019204 - FACTA Search

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

Blood transfusion or blood products are a important route for transmission of hepatitis C virus(HCV) infection. Routes of infection other than blood transfusion are medical treatments including hemodialysis, exposure of hospital employees to needles contaminated with blood, drug abusers, acupuncture, tattooing, certain types of sexual behavior and mother-to-infant infection. The prevalence of anti-HCV antibodies in blood donors in Kumamoto Prefecture was 1.30%(1,704 of 131,376) between February and October 1992 and 0.46%(622 of 132,847) between April 1998 and May 1999, respectively. Also, the prevalence of anti-HCV was 22.9%(126 of 550) in the highly endemic area. The prevalence of HCV infection was evaluated in 548 patients undergoing hemodialysis, and 216 members of the hospital dialysis staff. Of 548 hemodialysis patients, 166(30.3%) were positive and significantly higher than those for either hospital staff members(2.3%; p < 0.01) or healthy blood donors(1.3%; p < 0.01). Patients with a history of blood transfusion tended to have a higher positivity rate for anti-HCV than did the non-transfused group. Positivity for anti-HCV was related to the duration fo hemodialysis. Although hemodialysis patients remain a high-risk group for HCV infection, the prevalence of anti-HCV antibodies has decreased recently thanks to the use of erythropoietin for renal anemia, the universal screening of blood donors for anti-HCV antibodies, and improvements in infection control measures for this virus. To evaluate the effect of interferon(IFN) therapy on the incidence of hepatocellular carcinoma(HCC) or decompensated liver cirrhosis, 490 patients with chronic hepatitis or liver cirrhosis type C who had undergone liver biopsy since 1987, were followed periodically. Of these patients, 411 received IFN and 79 were untreated. The degree of liver fibrosis was assessed from stage F0(no fibrosis) to stage F4(cirrhosis). Response to IFN was determined virologically and biochemically. HCC developed in IFN-treated patients and in 17 untreated patients with stage F3 or F4 fibrosis. In multivariate analysis, IFN therapy was associated with a reduced risk of HCC, especially among patients with sustained virological response(CR), among those with persistently normal serum ALT levels, and among those with ALT levels less than two times the upper limit of normal(PR). Also, the cumulative incidence of decompensated liver cirrhosis and cumulative survival in treated and untreated patients differed significantly. None of the patients with CR or PR progressed to the decompensated state and all patients with CR or PR have survived to date. In conclusion, IFN therapy significantly reduces the risk for HCC or decompensated cirrhotic stage, especially among virological or biochemical responders.
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PMID:[Hepatitis C: epidemiology and therapy--with special reference to long-term prognosis after IFN therapy]. 1075 68

A role of the copper protein ceruloplasmin (Cp) in iron metabolism is suggested by its ferroxidase activity and by the tissue iron overload in hereditary Cp deficiency patients. In addition, plasma Cp increases markedly in several conditions of anemia, e.g. iron deficiency, hemorrhage, renal failure, sickle cell disease, pregnancy, and inflammation. However, little is known about the cellular and molecular mechanism(s) involved. We have reported that iron chelators increase Cp mRNA expression and protein synthesis in human hepatocarcinoma HepG2 cells. Furthermore, we have shown that the increase in Cp mRNA is due to increased rate of transcription. We here report the results of new studies designed to elucidate the molecular mechanism underlying transcriptional activation of Cp by iron deficiency. The 5'-flanking region of the Cp gene was cloned from a human genomic library. A 4774-base pair segment of the Cp promoter/enhancer driving a luciferase reporter was transfected into HepG2 or Hep3B cells. Iron deficiency or hypoxia increased luciferase activity by 5-10-fold compared with untreated cells. Examination of the sequence showed three pairs of consensus hypoxia-responsive elements (HREs). Deletion and mutation analysis showed that a single HRE was necessary and sufficient for gene activation. The involvement of hypoxia-inducible factor-1 (HIF-1) was shown by gel-shift and supershift experiments that showed HIF-1alpha and HIF-1beta binding to a radiolabeled oligonucleotide containing the Cp promoter HRE. Furthermore, iron deficiency (and hypoxia) did not activate Cp gene expression in Hepa c4 hepatoma cells deficient in HIF-1beta, as shown functionally by the inactivity of a transfected Cp promoter-luciferase construct and by the failure of HIF-1 to bind the Cp HRE in nuclear extracts from these cells. These results are consistent with in vivo findings that iron deficiency increases plasma Cp and provides a molecular mechanism that may help to understand these observations.
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PMID:Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. 1077 86

Both toxic exposure to cadmium and cancer therapy with cisplatin (CDDP) can induce anemia in patients owing to the insufficient production of erythropoietin (EPO). Therefore, the effects of cadmium chloride (Cd) and CDDP in the Hep3B human hepatoma cell line, which up-regulates EPO expression in response to hypoxia and cobalt (Co), were investigated. The induction of binding activity of the HIF-1 transcription factor and EPO mRNA expression and protein production were suppressed by Cd and CDDP in a dose-dependent manner with no apparent cell damage. Mercuric chloride also suppressed hypoxia- and Co-induced EPO production, mRNA expression, and HIF-1 binding in a manner similar to Cd and CDDP, whereas zinc chloride suppressed Co-induced EPO production, mRNA expression, and HIF-1 binding but did not affect hypoxia induction or that observed after simultaneous exposure to hypoxia and Co. In contrast, lead and tin salts had no effect on HIF-1 activation or EPO expression. These results indicate that Cd and CDDP have a strong and specific inhibitory effect on hypoxia- and Co-induced signaling and EPO induction in hepatic cells. It is likely that these agents cause anemia by directly impacting EPO production in the kidney. (Blood. 2000;96:3743-3747)
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PMID:Cadmium and platinum suppression of erythropoietin production in cell culture: clinical implications. 1109 55

Hemoperitoneum is a well-known form of hepatocellular carcinoma presentation and represents a frequent complication in countries with a high incidence of hepatocellular carcinoma, but it is rarely seen in Western countries. Our aim was to report the results and describe the arteriographic and CT-scan characteristics in a series of seven consecutive patients. They were admitted to our hospital because of hemoperitoneum due to ruptured tumor as a first manifestation of hepatocellular carcinoma, and the rupture was effectively controlled by transcatheter arterial embolization. From April 1989 to April 1998, 440 consecutive patients were admitted to our liver unit with the diagnosis of hepatocellular carcinoma and liver cirrhosis. Fourteen patients (3%) presented with acute hemoperitoneum due to tumor rupture as a first manifestation of hepatocellular carcinoma. We here report our experience in the group of patients treated by transcatheter arterial embolization. Mean age was 67.1+/-5 years (range, 61-73). All patients presented with sudden abdominal pain, abdominal distension, and four patients had symptoms of acute anemia. In all cases the ruptured tumor was subcapsular. The procedure was effective in the control of bleeding in all cases, without significant impairment in liver function or treatment-related deaths. In six of the seven patients, a self-limited postembolization syndrome was observed. Mean survival time was 273+/-488.7 days (range: 15-1290). Three patients survived more than six months but at the time of evaluation, only one patient was alive. In conclusion, the present results confirm that transcatheter arterial embolization is an effective and well-tolerated treatment in the management of hemoperitoneum due to ruptured hepatocellular carcinoma in patients with liver cirrhosis.
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PMID:Hemoperitoneum as a first manifestation of hepatocellular carcinoma in western patients with liver cirrhosis: effectiveness of emergency treatment with transcatheter arterial embolization. 1131 32

Spontaneous ruptures of a liver tumour are often considered as a potentially life-threatening situation. The aim of the present study was to evaluate both clinical features and treatment in a subgroup of patients with ruptured liver tumours. From 1995 to 2000, 20 patients were referred to our centre for spontaneous rupture of a liver tumour associated with haemoperitoneum. Hepatocellular carcinoma (HCC) was present in 13 patients (11 men and 2 women) aged from 48 to 72 years (mean 62) and adenoma in 7 women aged from 23 to 52 years (mean 35). Although all patients experienced sudden abdominal pain and anaemia, shock at admission was present in 4 (20%) patients including 3 with HCC. In patients with HCC, severe liver insufficiency (Child-Pugh C) was present in 5 cases including the 3 shocked patients. No treatment was undertaken in 2 patients, transarterial embolization was performed in 9 cases and 5 patients underwent delayed resection. In hospital, mortality was observed in 3 (23%) patients, all of them had severe liver insufficiency. Long-term survival was observed in patients with good liver function who underwent resection. In patients with adenoma, shock at admission was observed in only 1 patient under anticoagulation treatment. Emergency resection was performed in 3 cases. A decrease of the tumour size was observed in patients who underwent delayed resection resulting in a lower rate of peri-operative transfusion. In conclusion, this study confirms that the majority of patients with ruptured liver tumours had no evidence of haemodynamic instability and therefore should be initially managed conservatively. In patients with single ruptured HCC associated with good liver function, long-term survival can be observed after liver resection. Delayed resection facilitated the operative procedure in patients with ruptured adenoma.
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PMID:Management of spontaneous rupture of liver tumours. 1197 96

The anemia of chronic inflammatory and malignant diseases is partly due to impaired synthesis of the hormone erythropoietin (Epo). The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor a (TNF-alpha) suppress in vitro Epo gene expression and Epo protein secretion. However, the molecular mechanisms of this inhibition are poorly understood. The human Epo promoter and the 5' flanking region contain several recognition sequences for transcription factors acting either positively or negatively. Herein, we investigated the roles of the transcription factors GATA-2 and NF-kappaB in the modulation of Epo gene expression by IL-1beta and TNF-alpha in the human hepatoma cell line HepG2. Electrophoretic mobility shift assays revealed increased GATA-2 and NF-kappaB DNA binding in cells treated with IL-1beta or TNF-alpha. Reporter gene assays with a sequence from the Epo promoter in front of the firefly luciferase gene showed that the cytokines reduced Epo reporter gene activity. Functional inactivation of GATA-2 and NF-kappaB by oligo-decoy techniques prevented the inhibition of Epo production by IL-1beta and TNF-alpha. In HepG2 cells stably transfected with a dominant-negative form of IkappaBalpha, the activation of NF-kappaB was inhibited, while Epo mRNA levels and Epo secretion increased. Thus, both GATA-2 and NF-kappaB seem to be involved in the suppression of Epo gene expression by IL-1beta and TNF-alpha in vitro and may be responsible for impaired Epo synthesis in inflammatory diseases in vivo.
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PMID:Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. 1222 49

The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders.
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PMID:The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. 1237 Feb 82

2-Butoxyethanol is a member of a family of ethylene glycol monoalkyl ethers. It is used extensively as a solvent in surface coatings such as lacquers, enamels, varnishes, and latex paint; in paint thinners, paint stripping formulations, and inks; and in degreasers and industrial and household cleaners. 2-Butoxyethanol was nominated for study because of its widespread use in industrial and consumer applications, the potential for exposure to workers and the general population, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 2-butoxyethanol (greater than 99% pure) by inhalation (primary route of human exposure) for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and the bone marrow of male F344/N rats and B6C3F1 mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 14 weeks. One female rat in the 250 ppm group was killed moribund during week 8; four females in the 500 ppm group were killed moribund during week 1 and one during week 5. Final mean body weights of females exposed to 500 ppm were significantly less than those of the chamber controls. Clinical findings included abnormal breathing, pallor, red urine stains, nasal and eye discharge, lethargy, and increased salivation and/or lacrimation. Due to vascular thrombosis and infarction in the tail vertebrae of 500 ppm female rats, the tails became necrotic and either sloughed off or were chewed off. The primary effect on the hematopoietic system was an anemia characterized as macrocytic, normochromic, and regenerative in males exposed to 125 ppm or greater and, to a greater extent, in all exposed groups of females. Compared to the chamber controls, kidney weights of males exposed to 500 ppm and females exposed to 125 ppm or greater and liver weights of males exposed to 250 or 500 ppm and females exposed to 125 ppm or greater were significantly increased, and thymus weights of females exposed to 500 ppm were significantly less. In female rats killed moribund, there was considerable histologic evidence of thrombosis in tissues and organs including the nasal cavity, incisors, liver, lung, and heart. In addition to thrombosis, infarction occurred in the vertebrae of the tail resulting in necrosis and loss of the distal portion of the tail. There were also inflammation, necrosis, and ulceration of the forestomach; necrosis and centrilobular degeneration of the liver; renal tubule degeneration; and atrophy of the spleen and thymus. Exposure-related increases in the incidences of Kupffer cell pigmentation, forestomach inflammation and epithelial hyperplasia, bone marrow hyperplasia, splenic hematopoietic cell proliferation, and renal tubule pigmentation were observed in male and/or female rats surviving to the end of the study. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31, 62.5, 125, 250, or 500 ppm, 6 hours per day, 5 days per week for 14 weeks. Two male and two female mice exposed to 500 ppm died and two males and two females were killed moribund during the first 2 weeks of the study. Final mean body weights of 125, 250, and 500 ppm male mice were significantly less than those of the chamber controls. Clinical findings were observed only in 500 ppm males and females that died or were killed moribund and included abnormal breathing, red urine stains, and lethargy. Hematologic evaluation indicated an anemia that was characterized as normocytic, normochromic, and regenerative in mice exposed to 62.5 ppm or greater; the anemia was more pronounced in females. Liver weights of males exposed to 500 ppm were significantly greater than the chamber controls. In mice either dying early or killed moribund, there were inflammation, necrosis, and ulceration of the forestomach; mediastinal pleura and peritoneal inflammationmmation associated with the forestomach lesions; liver necrosis; renal tubule degeneration; atrophy of the spleen, thymus, and mandibular and mesenteric lymph nodes; and degeneration of the testis. Exposure-related increases in the incidences of hematopoietic cell proliferation and hemosiderin pigmentation of the spleen, Kupffer cell hemosiderin pigmentation of the liver, inflammation and epithelial hyperplasia of the forestomach, and renal tubule hemosiderin pigmentation occurred in male and/or female mice surviving to the end of the study. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 31.2, 62.5, or 125 ppm, 6 hours per day, 5 days per week for 104 weeks. For hematology and bone marrow analyses, additional groups of 27 male and 27 female rats were exposed to 0, 62.5, or 125 ppm for evaluation at 3, 6, and 12 months and nine male and nine female rats were exposed to 31.2 ppm for evaluation at 3 (hematology only) and 6 months. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber control groups. The mean body weights of females exposed to 125 ppm were generally less than the chamber control group. Hematology and Bone Marrow Cellularity: The most consistent exposure-related effect on the hematopoietic system was an exposure concentration-related mild macrocytic, normochromic, regenerative anemia present at 3, 6, and 12 months, with females more affected than males. Significant increases in bone marrow cellularity and decreases in the myeloid/erythroid ratio relative to the chamber controls were observed at all time points in females exposed to 125 ppm, and a decrease in the myeloid/erythroid ratio was observed in males exposed to 125 ppm at 12 months. Pathology Findings: The incidence of benign or malignant pheochromocytoma (combined) of the adrenal medulla in females exposed to 125 ppm was not significantly increased compared to the chamber controls but exceeded the historical control range. Exposure-related increases in the incidences of hyaline degeneration of the olfactory epithelium and Kupffer cell pigmentation of the liver were observed in male and female rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 2-butoxyethanol by inhalation at concentrations of 0, 62.5, 125, or 250 ppm, 6 hours per day, 5 days per week for 104 weeks. For hematology and bone marrow analyses, additional groups of 30 male and 30 female mice were exposed to 0, 62.5, 125, or 250 ppm for evaluation at 3, 6, and 12 months. Survival and Body Weights: Survival of male mice exposed to 125 or 250 ppm was significantly less than that of the chamber control group. The mean body weights of exposed males were generally less than those of the chamber control group during the last 6 months of the study. The mean body weights of exposed female mice were less than those of the chamber control group; the reductions were greater and occurred earlier than those observed in males. Hematology: The most consistent exposure-related effect on the hematopoietic system was an exposure concentration-related minimal normocytic, normochromic, regenerative anemia present at 3, 6, and 12 months, with females affected slightly more than males. Pathology Findings: In females exposed to 250 ppm, incidences of forestomach squamous cell papilloma and squamous cell papilloma or carcinoma (combined) were significantly increased relative to the chamber controls, and these incidences exceeded the ranges in historical chamber controls. In 2-butoxyethanol exposed males, there were possible exposure-related increases in the incidences of squamous cell papilloma of the forestomach, although the increases were not significant and the incidences were within the historical control range for chamber controls. Accompanying these neoplasms in females and, to a lesser extent, in males were exposure-related increases in the incidences of ulcer and epithelial hyperplasia of the forestomach. In male mice exposed to 250 ppm, the incidence of hemangiosarcoma of the liver was significantly increased relative to chamber controls and exceeded the range in historical controls; in addition, there were possible exposure-related increases in the incidence of hepatocellular carcinoma. Incidences of hemosiderin pigmentation in the Kupffer cells were significantly increased in 125 and 250 ppm males and all exposed groups of females. The incidences of splenic hematopoietic cell proliferation and hemosiderin pigmentation were generally increased in males and females, and the incidences of bone marrow hyperplasia were increased in males. The incidences of hyaline degeneration of the olfactory and respiratory epithelia of the nose were increased in female mice. GENETIC TOXICOLOGY: 2-Butoxyethanol did not induce mutations in any of the S. typhimurium strains tested, with or without induced hamster or rat liver S9. 2-Butoxyethanol induced cycle delay but did not induce either sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells with or without S9. 2-Butoxyethanol did not induce micronuclei in bone marrow cells of male rats or mice administered the chemical by intraperitoneal injection three times at 24-hour intervals. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5, or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on the increased combined incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on increased incidences of hemangiosarcoma of the liver. A marginal increase in the incidences of forestomach squamous cell papilloma and an increase in the incidences of hepatocellular carcinoma may have been exposure related. There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on increased incidences of fore stomach squamous cell papilloma or carcinoma (mainly papilloma). Increased incidences of forestomach neoplasms in male and female mice occurred in groups in which ulceration and hyperplasia were also present. Exposure to 2-butoxyethanol caused a mild regenerative anemia and effects secondary to the anemia. Synonyms: 2-Butoxy-1-ethanol; m-butyl ether; butyl glycol; ethylene glycol monobutyl ether Trade name: Butyl Cellosolve
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PMID:NTP Toxicology and Carcinogenesis Studies 2-Butoxyethanol (CAS NO. 111-76-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 79

Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor (TfR). A soluble form of the TfR (sTfR) has been identified in animal and human serum. Soluble TfR is a truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor. The erythroblasts rather than reticulocytes are the main source of serum sTfR. Serum sTfR levels average 5.0+/-1.0 mg/l in normal subjects but the various commercial assays give disparate values because of the lack of an international standard. The most important determinant of sTfR levels appears to be marrow erythropoietic activity which can cause variations up to 8 times below and up to 20 times above average normal values. Soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity, and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful to investigate the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing to predict response early when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be of considerable help in the differential diagnosis of microcytic anemia. This is particularly useful to identify concomitant iron deficiency in a patient with inflammation because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL) and high-grade non-Hodgkin's lymphoma and possibly hepatocellular carcinoma, sTfR levels are not increased in patients with malignancies. We conclude that soluble TfR represents a valuable quantitative assay of marrow erythropoietic activity as well as a marker of tissue iron deficiency.
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PMID:Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. 1258 62

Tetrafluoroethylene is used in the production of polytetrafluoroethylene (Teflon(R)) and other polymers. Tetrafluoroethylene was nominated by the National Cancer Institute for toxicity and carcinogenicity studies based on the potential for human exposure to the chemical due to the large production volume and on the lack of adequate data for tetrafluoroethylene in the literature. Male and female F344/N rats and B6C3F1 mice were exposed to tetrafluoroethylene (98% to 99% pure) by whole body inhalation exposure for 16 days, 13 weeks, or 2 years. Genetic toxicity studies were conducted in mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All rats survived to the end of the study. The final mean body weights and body weight gains of males and females exposed to 5,000 ppm were significantly less than those of the controls. The mean body weight gain of females exposed to 2,500 ppm was also significantly less than that of the controls. There were no exposure-related clinical findings in male or female rats. There were no significant differences in hematology parameters that were considered to be related to tetrafluoroethylene exposure. Absolute and relative kidney weights of all exposed groups of males were significantly greater than those of the controls, as were those of females in the 2,500 and 5,000 ppm groups. The absolute kidney weight of females exposed to 1,250 ppm was also significantly greater than that of the controls. The relative liver weights of all exposed groups of males and the absolute liver weights of males in the 625 and 2,500 ppm groups were significantly greater than those of the controls. Increased incidences of renal tubule degeneration occurred in males and females exposed to 625 ppm or greater; this lesion was located predominantly at the corticomedullary junction. The severity of degeneration increased with increasing exposure concentration and was slightly greater in males than females. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All mice survived to the end of the study. Final mean body weights and body weight gains of all exposed groups of mice were similar to those of the controls. There were no exposure-related clinical findings in male or female mice. There were no significant differences in hematology parameters that were considered to be related to tetrafluoroethylene exposure. The absolute and relative liver weights of females exposed to 5,000 ppm were significantly greater than those of the controls, as was the absolute kidney weight of females in that group and the absolute liver weight of females in the 2,500 ppm group. Renal tubule karyomegaly was observed in male and female mice in the 1,250, 2,500, and 5,000 ppm groups, and the severity of this lesion increased with increasing exposure concentration. Karyomegaly was located predominantly in the inner renal cortex. 13-WEEK STUDY IN RATS: Groups of 10 male and 9 or 10 female F344/N rats were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weight and body weight gain of males exposed to 5,000 ppm were significantly less than those of the controls, as was the mean body weight gain of females in this exposure group. There were no clinical findings attributed to exposure to tetrafluoroethylene. Exposure of rats to tetrafluoroethylene resulted in a concentration-dependent normocytic, normochromic, nonresponsive anemia consistent with a secondary hypoproliferative anemia. An exposure concentration-dependent proteinuria also occurred, consistent with renal tubule th renal tubule degeneration observed histopathologically. The absolute and relative liver weights of all exposed groups of males and of females in the 5,000 ppm group were significantly greater than those of the controls. The absolute and relative right kidney weights of males and females exposed to 1,250 ppm or greater and of females in the 625 ppm group were also significantly greater than those of the controls. There were no differences in sperm morphology or vaginal cytology parameters between control and exposed groups of rats. Incidences of renal tubule degeneration in males exposed to 625 ppm or greater and in females exposed to 2,500 or 5,000 ppm were significantly greater than those in the controls. Renal lesions were similar to those observed in the 16-day study and were located predominantly at the corticomedullary junction. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. Final mean body weights and body weight gains of all exposed groups of male and female mice were generally similar to those of the controls. There were no clinical findings that were considered to be related to tetrafluoroethylene exposure. Exposure of mice to tetrafluoroethylene resulted in a concentration-dependent normocytic, normochromic, nonresponsive anemia, consistent with a secondary hypoproliferative anemia, and in polyuria. Differences in sperm morphology parameters and estrous cycle lengths were not considered to be exposure related. Incidences of karyomegaly of the renal tubule epithelial cells in male and female mice exposed to 1,250 ppm or greater were significantly greater than those in the controls. Karyomegaly was similar to that observed in the 16-day study and was observed primarily in the inner renal cortex. 2-YEAR STUDY IN RATS: Groups of 60 male rats were exposed to 156, 312, or 625 ppm and groups of 60 female rats were exposed to 312, 625, or 1,250 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 104 weeks, with an observation period of 11 days following the final exposure. Ten male and ten female rats from each exposure group were evaluated at 15 months for organ weights and clinical pathology. Survival, Body Weights, and Clinical Findings: Survival rates of males in the 625 ppm group and of all exposed groups of females were significantly less than those of the controls. Mean body weights of males exposed to 625 ppm were lower than those of the controls from week 81 until the end of the study, and the mean body weight of 1,250 ppm females was slightly lower than that of the controls at the end of the study. The only clinical finding associated with exposure to tetrafluoroethylene was opacity of the eyes in exposed groups of female rats; this change was observed microscopically as cataracts. Hematology, Clinical Chemistry, and Urinalysis: At the 15-month interim evaluation, there were no differences in hematology, clinical chemistry, or urinalysis parameters that were considered to be related to tetrafluoroethylene exposure. Pathology Findings: The absolute and relative kidney weights of males exposed to 625 ppm and females exposed to 1,250 ppm and the absolute kidney weight of females exposed to 625 ppm were significantly greater than those of the controls at the 15-month interim evaluation. At 15 months, renal tubule hyperplasia was observed in one male exposed to 312 ppm and one male and one female exposed to 625 ppm; oncocytic hyperplasia was observed in one female exposed to 1,250 ppm. At the end of the study, incidences of renal tubule adenoma were greater in males and females exposed to 312 ppm or greater than those in the controls. This exposure-related increase was confirmed by examination of step sections (extended evaluations). At the end of the study, the incidences of renal tubule hyperplasia in males exposed to 625 ppm and females exposed to 1,250 ppm were significantly greater than those in the controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in the extended evaluations and in the standard and extended evaluations (combined) in the 1,250 ppm female group and the 625 ppm male group were significantly greater than those in the controls, and the incidences occurred with significant positive trends. Oncocytic hyperplasia was observed at the end of the study in one male exposed to 312 ppm and in three females exposed to 1,250 ppm. At 15 months and at the end of the study, the incidences of renal tubule degeneration in all exposed groups of males and in females in the 625 and 1,250 ppm groups were greater than those in the controls. Renal tubule degeneration was similar to that observed in the 13-week study and was located predominantly at the corticomedullary junction. The severity of nephropathy generally increased with increasing exposure concentration in male rats at 15 months and 2 years. The absolute and relative liver weights of females in the 1,250 ppm group and the absolute liver weight of females exposed to 625 ppm were significantly greater than those of the controls at the 15-month interim evaluation. At 2 years, the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined) in males exposed to 312 ppm, the incidences of hepatocellular adenoma and adenoma or carcinoma (combined) in females in all exposed groups, and the incidences of hepatocellular carcinoma in females exposed to 312 or 625 ppm were significantly greater than those in the controls. Also at 2 years, the incidence of hemangiosarcoma in females exposed to 625 ppm was significantly greater than that in the controls. In all exposed groups of males, the incidences of clear cell foci at 15 months were greater than those in the controls; at 2 years, the incidences of eosinophilic foci in all exposed groups of males and the incidences of basophilic and mixed cell foci in males in the 312 and 625 ppm groups were greater than those in the controls. The incidences of mixed cell foci at 15 months in females exposed to 625 or 1,250 ppm and at 2 years in females exposed to 1,250 ppm were also significantly greater than those in the controls. At the end of the 2-year study, increased incidences of cystic degeneration occurred in the liver of all exposed groups of males, and increased incidences of hepatic angiectasis were observed in exposed groups of females. Incidences of mononuclear cell leukemia in males exposed to 156 ppm and in all exposed groups of females were significantly greater than those in the controls. Incidences of cataracts in females exposed to 1,250 ppm were greater than those in the controls at the end of the 2-year study. At the end of the study, there were slight increases in the incidences of testicular interstitial cell adenoma in rats exposed to 312 or 625 ppm. 2-YEAR STUDY IN MICE: Groups of 58 male and 58 female B6C3F1 mice were exposed to 0, 312, 625, or 1,250 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week, for 95 to 96 weeks. Ten male and ten female mice from each exposure group were evaluated at 15 months for organ weights. Survival, Body Weights, and Clinical Findings: The survival rates of all exposed groups of males and females were significantly less than those of the controls. Because of the reduced survival due to exposure-related liver neoplasms, the study was terminated during week 96. Mean body weights of exposed groups of males and females were generally similar to those of the controls, except at the end of the study, when they were somewhat less than those of the controls. There were no clinical findings related to tetrafluoroethylene exposure. Pathology Findings: At the 15-month interim evaluation, there were no differences in absolute or relative kidney, liver, or lung weights between exposed and control groups of mice. At the end of the study, the incidences of multifocal coagulative necrosis of the liver were increased in males in the 625 and 1,250 ppm groups. Also at the end of the study, females in all exposed groups had greater incidences of hematopoietic cell proliferation in the liver than the controls. Angiectasis occurred in all exposed groups of males and females at 15 months and at the end of the study. At the 15-month interim evaluation, hemangiosarcomas were observed in three males exposed to 1,250 ppm and in one female exposed to 312 ppm. The incidences of hemangiosarcoma in all exposed groups of males and females at the end of the study were significantly greater than those in the controls and exceeded the historical chamber control ranges. Also at the end of the study, the incidences of hemangioma in males and females exposed to 312 ppm and in males exposed to 625 ppm were also significantly greater than those in the controls and exceeded the range in historical chamber controls. At 15 months, hepatocellular adenomas and carcinomas occurred in control males and all exposed groups of males and females. Females exposed to 625 or 1,250 ppm had significantly greater incidences of eosinophilic foci than the controls at the 15-month interim evaluation. At the end of the study, the incidences of eosinophilic foci in males exposed to 625 or 1,250 ppm and in females exposed to 312 or 625 ppm were significantly greater than those in the controls. In male and female mice, increased incidences of a variety of hepatocellular neoplasms, including adenomas, multiple adenomas, carcinomas, and multiple carcinomas, were considered related to tetrafluoroethylene exposure. At the end of the study, the incidences of histiocytic sarcoma (all organs) in all exposed groups of males and females were significantly greater than those in the controls and exceeded the historical control ranges for all organs. The greatest incidences of histiocytic sarcomas were observed in the liver and lung, but these neoplasms were also observed in the spleen, lymph nodes, bone marrow, and kidney. Significantly increased incidences of renal tubule dilatation (males) and karyomegaly (males and females), located predominantly in the inner cortex, were observed in mice exposed to 625 or 1,250 ppm at 15 months. At the end of the study, the increased incidences of dilatation and karyomegaly in all exposed groups of males and of karyomegaly in 1,250 ppm females were generally significant. Incidences of hematopoietic cell proliferation in the spleen of all exposed groups of males and females were significantly greater than those in the controls at the end of the study. Additionally, the severity of this lesion increased with increasing exposure concentration. GENETIC TOXICOLOGY: No increases in the frequency of micronucleated erythrocytes were observed in peripheral blood samples obtained from male and female mice at the end of the 13-week inhalation study of tetrafluoroethylene. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of tetrafluoroethylene in male F344/N rats based on increased incidences of renal tubule neoplasms (mainly adenomas) and hepatocellular neoplasms. There was clear evidence of carcinogenic activity of tetrafluoroethylene in female F344/N rats based on increased incidences of renal tubule neoplasms, liver hemangiosarcomas, hepatocellular neoplasms, and mononuclear cell leukemia. There was clear evidence of carcinogenic activity of tetrafluoroethylene in male and female B6C3F1 mice based on increased incidences of liver hemangiomas and hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas. Slight increases in the incidences of mononuclear cell leukemia and testicular interstitial cell adenomas in male rats may have been related to exposure to tetrafluoroethylene. Exposure of rats to tetrafluoroethylene resulted in increased incidences of renal tubule hyperplasia and degeneration in males and females, increased severity of kidney nephropathy in males, and increased incidences of liver angiectasis and cataracts in females. Exposure of mice to tetrafluoroethylene resulted in increased incidences of hematopoietic cell proliferation of the liver in females, liver angiectasis in males and females, renal tubule dilatation in males, renal tubule karyomegaly in males and females, and splenic hematopoietic cell proliferation in males and females. Synonyms: Perfluoroethylene; tetrafluoroethene; 1,1,2,2-tetrafluoroethylene; TFE
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PMID:NTP Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 116-14-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies). 1259 25

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