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:C0002871 (anemia)
52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

THIS STUDY WAS DESIGNED TO APPROACH TWO PRIMARY QUESTIONS CONCERNING HEMATOPOIETIC STEM CELLS (HSC) IN MICE: what is the concentration of HSC with extensive proliferative potential in marrow, and how long can an HSC continue to function in an intact animal? The assay system was the W/W(v) mouse, a mouse with an inherited HSC defect, reflected in a reduction in all myeloid tissue and most particularly in a macrocytic anemia.A single chromosomally marked HSC will reconstitute the defective hematopoietic system of the W/W(v). The concentration of HSC in normal littermate (+/+) marrow was assayed by limiting dilution calculation using cure of W/W(v) as an end point (correction of anemia and erythrocytes' macrocytosis) and found to be approximately 10/10(5). This is significantly less than spleen colony forming cell (CFU-S) concentration: approximately 220/10(5) in +/+ and ranging from 50 to 270/10(5) in various other studies. Blood values were studied at selected intervals for as long as 26 mo. Of 24 initially cured mice, which were observed for at least 2 yr, 75% remained cured. However, of all cured mice, 17 lost the cure, returning to a macrocytic anemic state. Cured mice had normal numbers of nucleated and granulocytic cells per humerus and a normal concentration of CFU-S. However, cure of secondary W/W(v) recipients by this marrow was inefficient compared with the original +/+ marrow. These studies suggest the CFU-S assay over-estimates extensively proliferating HSC or perhaps does not assay such a cell. A single such HSC can not only cure a W/W(v), but can sustain the cure for 2 yr or more, despite a relative deficit of cells capable of curing other W/W(v). However, the duration of sustained cure may be finite.
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PMID:Hematopoietic stem cells with high proliferative potential. Assay of their concentration in marrow by the frequency and duration of cure of W/Wv mice. 612 53

We have treated 38 patients with stage III/IV non-small cell lung cancer with the following regimen: mitomycin-C = 6 mg/m2, ifosfamide = 3 g/m2, cisplatin = 75 mg/m2, vindesine = 3 mg/m2 (MICE), intravenously (i.v.) on day 1, every 3 weeks. Among 26 patients with stage IV disease, 15 obtained a partial remission (PR) (response rate = 57%, 95% confidence interval = 38-76), with a median time to disease progression and a median survival of 4.9 and 7.1 months, respectively. 6 out 7 patients with stage IIIA disease were documented as PR and 5 of them underwent radical surgery with two pathologically confirmed complete remissions. Overall toxicity was substantial but manageable: 3 patients had grade III/IV leucopenia (although 5 patients had neutropenic fever) whereas 13 patients experienced grade II/II anaemia. In conclusion we believe that MICE regimen is an interesting combination and warrants further evaluations both for palliation and in a neoadjuvant setting.
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PMID:MICE: a new active combination for non-small cell lung cancer. 826 Feb 39

Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. The final mean body weights were similar among exposed and chamber control groups. Compared to chamber controls, the lung weights of males and females exposed to 10 mg/m(3) or greater were increased. Gallium ar senide particles were visible in alveolar spaces and macrophages in some mice exposed to 150 mg/m(3). Moderate proteinosis, mild epithelial hyperplasia, and histiocytic infiltration of the lung were observed in males and females exposed to 10 mg/m(3) or greater. In the larynx, mild squamous metaplasia was seen in mice exposed to 10 mg/m(3) or greater, and mild chronic inflammation occurred in mice exposed to 75 or 150 mg/m(3). 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. The final mean body weight and body weight gain of males exposed to 75 mg/m(3) were significantly less than those of the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in exposed groups of rats. There were also increases in platelet and neutrophil counts, a transient decrease in leukocyte counts, and increases in the serum activities of alanine aminotransferase and sorbitol dehydrogenase. These changes were of greater magnitude in male rats. The lung weights of all exposed groups of rats were increased, while testis, cauda epididymis, and epididymis weights of males exposed to 37 or 75 mg/m(3) were generally less than those of chamber controls. Total spermatid heads and spermatid counts were significantly decreased in males exposed to 75 mg/m(3), while epididymal spermatozoa motility was significantly reduced in males ees exposed to 10 mg/m(3) or greater. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of exposed rats. Minimal to marked proteinosis and minimal histiocytic cellular infiltration of the alveoli were observed in all exposed groups; minimal squamous metaplasia in the larynx and lymphoid cell hyperplasia of the mediastinal lymph node were observed in some males and females exposed to 37 or 75 mg/m(3). Exposure-related increases in the incidences of plasma cell hyperplasia of the mandibular lymph node, testicular atrophy, epididymal hypospermia, bone marrow hyperplasia (males), and hemosiderosis in the liver were observed in the 37 and 75 mg/m(3) groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 1, 10, 37, or 75 mg/m(3), 6 hours per day, 5 days per week, for 14 weeks. One female mouse exposed to 75 mg/m(3) died before the end of the study. Final mean body weights and body weight gains of males in the 75 mg/m(3) group were signifi cantly less than the chamber controls. Hematology and clinical chemistry results indicated that exposure to gallium arsenide affected the circulating erythroid mass and induced a microcytic responsive anemia with an erythrocytosis and increased zinc protoporphyrin/heme ratios in male and female mice. There were also increases in platelet and neutrophil counts. Compared to the chamber controls, the lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased. Testis, cauda epididymis, and epididymis weights, total spermatid heads, spermatid counts, and concentration and motility of epididymal spermatozoa were generally decreased. Gallium arsenide particles were visible in alveolar spaces and macrophages in the lungs of mice exposed to 1 mg/m(3) or greater. Mild to marked proteinosis, histiocytic infiltration, and epithelial hyperplasia were observed in the alveoli of males and females exposed to 1 mg/m(3) or greater. Minimal to mild suppurative inflammation and granuloma in the lung and squamous metaplasia in the larynx were present in males and females exposed to 10 mg/m(3) or greater. Min imal hyperplasia was observed in the tracheobronchial lymph node of males exposed to 10 mg/m(3) or greater and females exposed to 37 or 75 mg/m(3). Exposure- related increases in the incidences of testicular atrophy, epididymal hypospermia, hematopoietic cell proliferation of the spleen, and hemosiderosis of the liver and spleen were observed in groups of male and female mice exposed to 10 mg/m(3) or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.01, 0.1, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights: Survival of exposed male and female rats was similar to the chamber controls. Mean body weights of males exposed to 1.0 mg/m(3) were generally less than those of the chamber controls throughout the study; females exposed to 1.0 mg/m(3) had slightly lower mean body weights during the second year. Pathology Findings: Compared to the chamber controls, the incidences of alveolar/bronchiolar neoplasms were significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control ranges. Exposure-related nonneoplastic lesions in the lungs of male and female rats included atypical hyperplasia, alveolar epithelial hyperplasia, chronic active inflammation, proteinosis, and alveolar epithelial metaplasia. In the larynx of males exposed to 1.0 mg/m(3), the incidences of hyperplasia, chronic active inflammation, squamous metaplasia, and hyperplasia of the epiglottis were significantly increased. The incidences of benign pheochromocytoma of the adrenal medulla occurred with a positive trend in female rats, and the incidence was significantly increased in the 1.0 mg/m(3) group and exceeded the historical control range. The incidence of mononuclear cell leukemia was significantly increased in females exposed to 1.0 mg/m(3) and exceeded the historical control range. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed by inhalation to gallium arsenide particulate at concentrations of 0, 0.1, 0.5, or 1.0 mg/m(3), 6 hours per day, 5 days per week, for 105 (males) or 106 (females) weeks. Survival and Body Weights: Survival of male and female mice was similar to the chamber controls. Mean body weights of exposed groups of males were similar to those of the chamber controls throughout the study; mean body weights of exposed groups of females were greater than those of the chamber controls from week 13 until the end of the study. Pathology Findings: Exposure-related nonneoplastic lesions in the lung of all groups of exposed mice included suppurative focal inflammation, chronic focal inflammation, histiocyte cellular infiltration, alveolar epithelial hyperplasia, and proteinosis. Increased incidences of minimal lymphoid hyperplasia of the tracheobronchial lymph node occurred in mice exposed to 1.0 mg/m(3) and in 0.5 mg/m(3)mg/m(3) males. GENETIC TOXICOLOGY: Gallium arsenide was not mutagenic in several strains of Salmonella typhimurium, with or without S9 metabolic activation enzymes, and no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to gallium arsenide by inhalation for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of gallium arsenide in male F344/N rats exposed to 0.01, 0.1, or 1.0 mg/m(3). There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of benign and malignant neoplasms in the lung. Increased incidences of benign neoplasms of the adrenal medulla and increased incidences of mononuclear cell leukemia were also considered to be exposure related. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 0.1, 0.5, or 1.0 mg/m(3). Exposure to gallium arsenide caused a spectrum of nonneoplastic lesions in the lung of rats and mice, the larynx of male rats and hyperplasia of the tracheobronchial lymph node in mice. Synonym: Gallium monoarsenide.
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PMID:NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1256 48

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

1-Chloro-2-propanol and its positional isomer, 2-chloro-1-propanol, are used as chemical intermediates for the manufacture of propylene oxide, a starting material for production of polyurethane polyols and propylene glycol. The National Cancer Institute nominated 1-chloro-2-propanol for study because of potential for human exposure due to its residues in various foods that are fumigated with ethylene oxide or propylene oxide. Male and female F344/N rats and B6C3F1 mice were exposed to technical grade 1-chloro-2-propanol (75% to 76%% 1-chloro-2-propanol; 24% to 25%% 2-chloro-1-propanol) in drinking water for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. Continuous breeding studies were conducted in Sprague-Dawley rats. 14-DAY STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. Two 10,000 ppm females died before the end of the study. The final mean body weights and body weight gains of 3,300 and 10,000 ppm rats were significantly less than those of the controls; rats in the 10,000 ppm groups lost weight. Water consumption by the 3,300 and 10,000 ppm groups was significantly less than that by the controls throughout the study. The thymus weights of 10,000 ppm rats were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused cytoplasmic alteration and degeneration of the acinar cells and fatty change in the pancreas, atrophy of the bone marrow, and atrophy and hematopoiesis of the spleen in males and females. 14-DAY STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 100, 330, 1,000, 3,300, or 10,000 ppm for 14 days. One male mouse in the 10,000 ppm group died before the end of the study. Mean body weight gains of 10,000 ppm mice were significantly less than those of the controls. Water consumption by 3,300 and 10,000 ppm males and females was significantly less than that by the controls throughout the study. Liver weights of 1,000, 3,300, or 10,000 ppm males and females were significantly greater and thymus weights of 10,000 ppm mice were significantly less than those of the controls. Exposure to 1-chloro-2-propanol caused hepatocellular vacuolization, cytoplasmic alteration and degeneration of the pancreas acinar cells, and atrophy of the spleen in males and females. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 1-chloro-2-propanol at concentrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 10, 35, 100, or 220 mg/kg) for 14 weeks. All rats survived to the end of the study. Mean body weight gains of 3,300 ppm rats were significantly less than those of the controls. Water consumption by the 3,300 ppm male and female rats was significantly less than that by the controls. A minimal to mild anemia was observed in exposed female rats. The cauda epididymis and epididymis weights of 3,300 ppm males were significantly less than those of the controls. The percentage of abnormal sperm in 3,300 ppm males and the concentration of epididymal sperm in 330 ppm males were significantly increased compared to the controls. Kidney and liver weights of males and females exposed to 100 ppm or more were generally greater than those of the controls. The incidences of acinar cell degeneration and fatty change of the pancreas in 1,000 and 3,300 ppm rats, hepatocytic metaplasia of the pancreatic islets in 3,300 ppm females, cytoplasmic vacuolization of the liver in 100, 1,000 and 3,300 ppm males, and renal tubule epithelium regeneration in 3,300 ppm females were increased compared to the controls. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 1-chloro-2-propanol in drinking water at concentrations of 0, 33, 100, 33entrations of 0, 33, 100, 330, 1,000, or 3,300 ppm (equivalent to average daily doses of approximately 5, 15, 50, 170, or 340 mg/kg to males and 7, 20, 70, 260, or 420 mg/kg to females) for 14 weeks. One 330 ppm male died before the end of the study. Mean body weight gains of exposed groups were similar to those of the controls. A minimal anemia was observed in 3,300 ppm males. The right epididymis weight of 3,300 ppm males was significantly greater than that of the controls. Kidney weights of 3,300 ppm mice, liver weights of 1,000 ppm males and of all exposed groups of females, and thymus weights of 1,000 and 3,300 ppm females were greater than those of the controls. The incidences of pancreatic acinar cell degeneration and fatty change in 3,300 ppm males and females and cytoplasmic vacuolization of the liver in all groups of exposed females were significantly increased compared to the controls. The severities of renal tubule cytoplasmic vacuolization were greater in 1,000 and 3,300 ppm males than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were administered drinking water containing 0, 150, 325, or 650 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 15, 30, or 65 mg/kg during the first several months of the study and 8, 17, or 34 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. Mean body weights of exposed rats were generally similar to those of the controls throughout most of the study. Water consumption by all exposed groups was similar to that by the controls. No treatment-related neoplasms or nonneoplastic lesions were observed in this study. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were administered drinking water containing 0, 250, 500, or 1,000 ppm 1-chloro-2-propanol (equivalent to average daily doses of approximately 45, 75, or 150 mg/kg to males and 60, 105, or 210 mg/kg to females during the first several months of the study and 25, 50, or 100 mg/kg for the remainder of the 2-year study) for up to 105 weeks. Survival of all exposed groups was similar to that of the controls. The mean body weights of all exposed mice were generally similar to those of the controls throughout the study. Water consumption by all exposed groups was similar to that by the controls. No treatment- related neoplasms or nonneoplastic lesions were observed in this study. GENETIC TOXICOLOGY: 1-Chloro-2-propanol is a demonstrated mutagen in vitro. It was weakly mutagenic in S. typhimurium strain TA100 in the presence of hamster or rat liver S9 activation enzymes and was positive, with and without S9, in TA1535. No mutagenic activity was detected in strains TA97, TA98, and TA1537, with or without S9. In cytogenetic tests with Chinese hamster ovary cells, 1-chloro-2-propanol induced high levels of sister chromatid exchanges and chromosomal aberrations in the presence and the absence of S9. The marked ability of 1-chloro-2-propanol to induce chromosomal effects in vitro was not seen in vivo. Positive results were obtained in a test in D. melanogaster for induction of sex-linked recessive lethal mutations in germ cells of males administered 1-chloro-2-propanol via injection; however, negative results were obtained when males were administered 1-chloro-2-propanol in feed. A subsequent germ cell reciprocal translocation test in D. melanogaster yielded negative results. Further, no induction of micronucleated erythrocytes was observed in peripheral blood of male and female mice administered 1-chloro-2-propanol via drinking water for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female F344/N rats exposed to 150, 325, or 650 ppm. There was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female B6C3F1 mice exposed to 250, 500, or 1,000 ppm. Synonyms: 1-Chloro-2-hydroxypropane, 1-chloroisopropyl alcohol, propylene-α-chlorohydrin, sec-propylene chlorohydrin
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Chloro-2-propanol (Technical Grade) (CAS NO. 127-00-4) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies. 1257 86

Pyridine is used as a denaturant in alcohol and anti freeze mixtures, as a solvent for paint, rubber, and polycarbonate resins, and as an intermediate in the manufacture of insecticides, herbicides, and fungicides. It is used in the production of piperidine, an intermediate in the manufacture of rubber and mepiquat chloride, and as an intermediate and solvent in the preparation of vitamins and drugs, dyes, textile water repellants, and flavoring agents in food. Pyridine was nominated for study because of its large production volume and its use in a variety of food, medical, and industrial products. Male and female F344/N rats, male Wistar rats, and male and female B6C3F1 mice were exposed to pyridine (approximately 99% pure) in drinking water for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 13-WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female F344/N rats were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 5, 10, 25, 55, or 90 mg pyridine/kg body weight). Two females exposed to 1,000 ppm died during week 1. Final mean body weights of 1,000 ppm males and females and 500 ppm females were significantly less than controls. Water consumption by female rats exposed to 1,000 ppm was less than that by controls. At study termination, evidence of anemia persisted in the 500 and 1,000 ppm males and all exposed groups of females. There was evidence of hepatocellular injury and/or altered hepatic function demonstrated by increased serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentrations in 500 and 1,000 ppm rats. The estrous cycle length of 1,000 ppm females was significantly longer than that of the controls. Liver weights of males and females exposed to 250 ppm or greater were significantly greater than controls. In the liver, the incidences of centrilobular degeneration, hypertrophy, chronic inflammation, and pigmentation were generally increased in 500 and 1,000 ppm males and females relative to controls. In the kidney, the incidences of granular casts and hyaline degeneration (hyaline droplets) were significantly increased in 1,000 ppm males and slightly increased in 500 ppm males; these lesions are consistent with 2u-globulin nephropathy. Additionally, there were increased incidences and/or severities of protein casts, chronic inflammation, mineralization, and regeneration primarily in 500 and 1,000 ppm males. 13-WEEK STUDY IN MALE WISTAR RATS: Groups of 10 male Wistar rats were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 5, 10, 30, 60, or 100 mg/kg). One male rat exposed to 500 ppm died during week 1. Final mean body weights of rats exposed to 250, 500, or 1,000 ppm were significantly less than those of the controls. Water consumption by rats exposed to 1,000 ppm was lower than that by controls. There was evidence of hepatocellular injury and/or altered hepatic function in the 500 and 1,000 ppm groups, similar to that observed in the 13-week study in F344/N rats. Incidences of centrilobular degeneration, hypertrophy, chronic inflammation, and pigmentation in the liver of rats exposed to 500 or 1,000 ppm were significantly increased relative to controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 50, 100, 250, 500, or 1,000 ppm (equivalent to average daily doses of 10, 20, 50, 85, or 160 mg/kg for males and 10, 20, 60, 100, or 190 mg/kg for females). One female mouse exposed to 250 ppm died during week 2. Final mean body weights of female mice exposed to 1,000 ppm were significantly less than those of controls. Water consumption by exposed female mice was lower than that by controls at week 1 but generally slightly higher than controls at week 13. Sperm motirm motility in exposed male mice was significantly decreased relative to controls. Liver weights were significantly increased relative to controls in males exposed to 100 ppm or greater and in 250 and 500 ppm females. No chemical-related lesions were observed in male or female mice. 2-YEAR STUDY IN F344/N RATS: Groups of 50 male and 50 female F344/N rats were exposed to pyridine in drinking water at concentrations of 0, 100, 200, or 400 ppm (equivalent to average daily doses of 7, 14, or 33 mg/kg) for 104 (males) or 105 (females) weeks. Survival, Body Weights, and Water Consumption Survival of exposed males and females was similar to that of controls. Mean body weights of 400 ppm males and females were generally less than those of the controls throughout the study, and those of 200 ppm males and females were less during the second year of the study. Water consumption by males and females exposed to 200 or 400 ppm was generally greater than that by controls. Pathology Findings Incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in male rats exposed to 400 ppm were significantly increased compared to controls and exceeded the historical control ranges. The findings from an extended evaluation (step section) of the kidneys did not reveal additional carcinomas, but additional adenomas were observed in each group of males. In the standard evaluation, an increased incidence of renal tubule hyperplasia was observed in 400 ppm males compared to controls. Incidences of mononuclear cell leukemia in female rats were significantly increased in the 200 and 400 ppm groups, and the incidence in the 400 ppm group exceeded the historical control range. Exposure concentration-related nonneoplastic liver lesions were observed in males and females, and the incidences were generally increased in groups exposed to 400 ppm. These included centrilobular cytomegaly, cytoplasmic vacuolization, periportal fibrosis, fibrosis, centrilobular degeneration and necrosis, and pigmentation. Bile duct hyperplasia occurred more often in exposed females than in controls. 2-YEAR STUDY IN MALE WISTAR RATS: Groups of 50 male Wistar rats were exposed to pyridine in drinking water at concentrations of 0, 100, 200, or 400 ppm (equivalent to average daily doses of 8, 17, or 36 mg/kg) for 104 weeks. Survival, Body Weights, and Water Consumption Survival of rats exposed to 200 or 400 ppm was significantly less than that of the controls. Mean body weights of rats exposed to 100, 200, or 400 ppm were significantly less than controls. Water consumption was similar by control and exposed rats. Pathology Findings The incidence of testicular interstitial cell adenoma in rats exposed to 400 ppm was significantly increased compared to controls. Incidences of interstitial cell hyperplasia were observed in control and exposed groups and were slightly, but not significantly, increased in rats exposed to 200 or 400 ppm. Severity of nephropathy was marked in all groups, and additional evidence of kidney disease, including mineralization in the glandular stomach, parathyroid gland hyperplasia, and fibrous osteodystrophy, was observed in 100 and 200 ppm rats. The incidences of hepatic centrilobular degeneration and necrosis, fibrosis, periportal fibrosis, and/or pigmentation were increased in one or more exposed groups. 2-YEAR STUDY IN MICE: Groups of 50 male B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 250, 500, or 1,000 ppm (equivalent to average daily doses of 35, 65, or 110 mg/kg) for 104 weeks, and groups of 50 female B6C3F1 mice were exposed to pyridine in drinking water at concentrations of 0, 125, 250, or 500 ppm (equivalent to average daily doses of 15, 35, or 70 mg/kg) for 105 weeks. Survival, Body Weights, and Water Consumption Survival of exposed males and females was similar to that of the controls. Mean body weights of 250 and 500 ppm females were less than controls. Water consumption by males exposed to 250 or 500 ppm was generally greater than that by controls during the last year of the study; male mice exposed to 1,000 ppm consumed less water than controls throughout the study. Water consumption by exposed females was generally lower than that by controls during the first year of the study, but greater than controls during the second year. Pathology Findings Hepatocellular neoplasms, including hepatoblastomas, in exposed male and female mice were clearly related to pyridine exposure. Additionally, many mice had multiple hepatocellular neoplasms. The incidences of hepatocellular neoplasms in exposed males and females generally exceeded the historical control ranges for drinking water studies. Neoplasms from control mice, 1,000 ppm males, and 500 ppm females were negative when stained for p53 protein. GENETIC TOXICOLOGY: Pyridine was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 or in L5178Y mouse lymphoma cells, with or without S9 metabolic activation, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. Pyridine was tested for induction of sex-linked recessive lethal mutations in adult male Drosophila melanogaster, and mixed results were obtained. In one experiment, administration by injection gave negative results, but feeding produced an equivocal response. A second experiment generated negative results by injection and feeding. A third experiment showed significant increases in sex-linked recessive lethal mutations in flies treated with pyridine by injection but not by feeding. Overall, results of the sex-linked recessive lethal mutations test in Drosophila melanogaster were considered negative by feeding and equivocal by injection. Results of a single reciprocal translocation test in male Drosophila melanogaster were negative. No induction of chromosomal aberrations or micronuclei was noted in bone marrow cells of male mice administered pyridine via intraperitoneal injection. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was some evidence of carcinogenic activity of pyridine in male F344/N rats based on increased incidences of renal tubule neoplasms. There was equivocal evidence of carcinogenic activity of pyridine in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was equivocal evidence of carcinogenic activity in male Wistar rats based on an increased incidence of interstitial cell adenoma of the testis. There was clear evidence of carcinogenic activity of pyridine in male and female B6C3F1 mice based on increased incidences of malignant hepatocellular neoplasms. In F344/N rats, exposure to pyridine resulted in increased incidences of centrilobular cytomegaly and degeneration, cytoplasmic vacuolization, and pigmentation in the liver of males and females; periportal fibrosis, fibrosis, and centrilobular necrosis in the liver of males; and bile duct hyperplasia in females. In male Wistar rats, pyridine exposure resulted in increased incidences of centrilobular degeneration and necrosis, fibrosis, periportal fibrosis, and pigmentation in the liver, and, secondary to kidney disease, mineralization in the glandular stomach and parathyroid gland hyperplasia. Synonyms: Azabenzene, azine
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PMID:NTP Toxicology and Carcinogenesis Studies of Pyridine (CAS No. 110-86-1) in F344/N Rats, Wistar Rats, and B6C3F1 Mice (Drinking Water Studies). 1257 3

Nitromethane is used as a rocket and engine fuel; as a synthesis intermediate for agricultural fumigants, biocides, and other products; as a solvent; and as an explosive in mining, oil-well drilling, and seismic exploration. It has been detected in air, in surface and drinking water, and in cigarette smoke. Nitromethane was studied because of the potential for widespread human exposure and because it is structurally related to the carcinogens 2-nitropropane and tetranitromethane. Male and female F344/N rats and B6C3F1 mice received nitromethane (purity 98% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived until the end of the study. The mean body weight gain of male rats in the 1,500 ppm group was slightly but significantly less than that of the controls; the final mean body weights and mean body weight gains of exposed females were similar to those of the controls. Clinical findings in all male and female rats in the 1,500 ppm groups included increased preening, rapid breathing, hyperactivity early in the study, and hypoactivity and loss of coordination in the hindlimbs near the end of the study. The relative liver weights of all exposed groups of male rats and the absolute and relative liver weights of females exposed to 375 ppm or greater were significantly greater than those of the controls. Minimal to mild degeneration of the olfactory epithelium was observed in the nose of males and females exposed to 375 ppm or greater. Sciatic nerve degeneration was present in all male and female rats exposed to 375 ppm or greater; rats exposed to 750 or 1,500 ppm also had reduced myelin around sciatic axons. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All mice survived to the end of the study. The final mean body weights and weight gains of exposed males and females were similar to those of the controls. Clinical findings included hypoactivity and tachypnea in male and female mice in the 1,500 ppm groups. Absolute and relative liver weights of male mice in the 750 and 1,500 ppm groups and female mice in all exposed groups and the relative liver weight of males in the 375 ppm group were significantly greater than those of the controls. Degeneration of the olfactory epithelium of the nose was observed microscopically in all males and females exposed to 375 ppm or greater; this lesion was of minimal severity in males and minimal to mild severity in females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 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 weight gain of male rats in the 1,500 ppm group were significantly less than those of the controls. Clinical findings included hindlimb paralysis in rats in the 750 and 1,500 ppm groups. Inhalation exposure of rats to nitromethane resulted in an exposure concentration-dependent, microcytic, responsive anemia; anemia was most pronounced in males and females exposed to 375 ppm or greater. The presence of schistocytes, Heinz bodies, and spherocytes and increased mean cell hemoglobin concentration and methemoglobin concentration were evidence that a hemolytic process was occurring; this hemolytic process could have accounted, in part, for the anemia. Thrombocytosis accompanied the anemia and would be consistent with a reactive bone marrow or could have been due to the erroneous inclusion of small erythrocyte fragments as part of the platelet count. On day 23, transient decreases in serum triiodothyronine, thyroxine, and fr and free thyroxine were observed in male rats exposed to 375 ppm or greater and female rats exposed to 750 or 1,500 ppm. There was little or no pituitary response to the thyroid hormone decreases, as evidenced by the lack of significantly increased concentrations of thyroid-stimulating hormone in exposed rats. No biologically significant differences in organ weights were observed. The forelimb and hindlimb grip strengths of males in the 1,500 ppm group were significantly less than those of the controls. The hindlimb grip strengths of females in the 750 and 1,500 ppm groups were also significantly less than the control value. Minimal to mild hyperplasia of the bone marrow was observed microscopically in male rats in the 750 and 1,500 ppm groups and in females exposed to 188 ppm or greater. Nasal lesions in exposed males and females included olfactory epithelial degeneration in males and females exposed to 375 ppm or greater and in one female exposed to 188 ppm and respiratory epithelial hyaline droplets and goblet cell hyperplasia in males and females in the 750 and 1,500 ppm groups; the severity of nasal lesions in males and females was minimal to mild. Males and females exposed to 375 ppm or greater had minimal to mild degeneration of the sciatic nerve and the lumbar spinal cord. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights and weight gains of exposed mice were generally similar to those of the controls. There were no treatment-related clinical findings. The absolute right kidney weights of all groups of exposed male mice except the 1,500 ppm group and of females exposed to 188 ppm or greater and the relative right kidney weights of all groups of exposed males and of females in the 750 and 1,500 ppm groups were significantly greater than those of the controls. The absolute liver weight of male mice in the 750 ppm group and the relative liver weights of males exposed to 375 ppm or greater were significantly greater than those of the controls. Olfactory epithelial degeneration and respiratory epithelial hyaline droplets were observed microscopically in all male and female mice exposed to 375 ppm or greater. Degeneration also occurred in females in the 188 ppm group, and hyaline droplets occurred in females in the 94 and 188 ppm groups. The average severity of the nasal lesions ranged from minimal to mild in males. In females, the average severity of olfactory epithelial degeneration ranged from minimal to mild and the severity of respiratory epithelial hyaline droplets ranged from minimal to moderate. All males and nine females in the 1,500 ppm groups also had minimal extramedullary hematopoiesis of the spleen. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 94, 188, or 375 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and Clinical Findings: There were no significant differences in survival rates between exposed and control male or female rats. The mean body weight of females in the 375 ppm group was slightly greater than that of the control group; the mean body weights of exposed males were generally similar to the mean body weight of the controls throughout the study. Clinical findings were consistent with incidences of mammary gland neoplasms in females exposed to 188 or 375 ppm; no hindlimb paralysis, as occurred in rats in the 13-week study, was observed in male or female rats in the 2-year study. Pathology Findings: The incidences of mammary gland fibroadenoma and fibroadenoma, adenoma, or carcinoma (combined) in female rats in the 188 and 375 ppm groups were significantly greater than those in the controls. Additionally, the incidences of mammary gland carcinoma in the 375 ppm group were significantly greater than those in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 188, 375, or 750 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and ClinicalFindings The survival rate of females in the 750 ppm group was marginally greater than that of the controls. The mean body weights of exposed females were generally slightly greater than the mean body weights of the controls during the study but were generally similar to the mean body weight of the controls at the end of the study. The mean body weights of exposed males were similar to those of the controls throughout the study. Clinical findings included swelling around the eyes and exophthalmos in exposed males and females; these findings were coincident with harderian gland neoplasms. Pathology Findings: The incidences of harderian gland adenoma and adenoma or carcinoma (combined) in exposed mice increased with increasing exposure concentration and were significantly greater in males and females in the 375 and 750 ppm groups than those in the controls. The incidences of harderian gland carcinoma in males and females in the 375 and 750 ppm groups were also slightly greater than those in the controls. Female mice in the 188 and 750 ppm groups had significantly greater incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) than the controls. The incidences of liver eosinophilic focus increased with increasing exposure concentration, and the incidences in the 375 and 750 ppm groups were significantly greater than the control incidence. The incidences of alveolar/bronchiolar carcinoma in male mice in the 750 ppm group and female mice in the 375 ppm group were significantly greater than those in the controls. Females in the 750 ppm group also had a significantly greater incidence of alveolar/bronchiolar adenoma or carcinoma (combined) and a slightly greater incidence of alveolar/bronchiolar adenoma than the controls. Females in the 375 ppm group had a significantly greater incidence of cellular infiltration of histiocytes in the lung than the controls. The incidences of degeneration and metaplasia of the olfactory epithelium and hyaline degeneration of the respiratory epithelium were significantly greater in exposed male and female mice than those in the controls. Additionally, males in the 375 and 750 ppm groups had significantly greater incidences of inflammation of the nasolacrimal duct than did the controls. GENETIC TOXICOLOGY: Nitromethane was not mutagenic in any tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, with or without S9 metabolic activation, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to nitromethane was noted with or without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice at the end of the 13-week inhalation study of nitromethane. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1 mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1 mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. Exposure to nitromethane by inhalation for 2 years resulted in increased incidences of nasal lesions including degeneration and metaplasia of the olfactory epithelium and degeneration of the respiratory epithelium in male and female mice. Synonym: Nitrocarbol
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PMID:NTP Toxicology and Carcinogenesis Studies of Nitromethane (CAS No. 75-52-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1258 15

Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentrations, occurred in 2,700 mg/kg male and female rats. The absolute and relative thymus weights of male rats receiving,350 or 2,700 mg/kg and female rats receiving 2,700 mg/kg were significantly lower than those of controls. At necropsy, all dosed rats had enlarged cecae/large intestines. Male rats receiving 1,350 mg/kg and male and female rats receiving 2,700 mg/kg had red, enlarged thyroid glands. Chemical-related microscopic lesions were present in the forestomach, thymus, thyroid gland, and pituitary gland. Minimal to mild hyperplasia of the forestomach mucosa was present in the 1,350 and 2,700 mg/kg male and female groups. Lymphoid depletion was observed in the thymus of three male and three female rats in the 2,700 mg/kg groups. Male and female rats receiving 1,350 and 2,700 mg/kg had thyroid gland follicular cell hyperplasia and an increase in thyroid-stimulating hormone producing cells in the pars distalis of the pituitary gland. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. There were no chemical-related deaths, and final mean body weights of dosed mice were similar to those of controls. No chemical-related clinical findings were noted for male or female mice. There were no differences in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice. There were no biologically significant differences in absolute or relative organ weights between dosed and control male and female mice. At necropsy, male mice receiving 2,700 mg/kg had enlarged cecae/large intestines. There were no biologically significant histopathologic lesions attributed to salicylazosulfapyridine administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 84, 168.8, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All rats survived to the end of the study. The finaludy. The final mean body weights of dosed male rats were similar to those of controls; the final mean body weights and body weight gains of dosed females were significantly lower than those of controls. No chemical-related clinical findings were noted in dosed male or female rats during the 13-week study. No significant differences in hematology or urinalysis parameters between control and dosed rats were observed. The absolute and relative right kidney weights of 337.5 mg/kg females were significantly greater than those of controls. At necropsy, some 337.5 mg/kg male rats had red, enlarged thyroid glands. Histopathologic changes were noted primarily in the thyroid gland and pituitary gland of males and females in the 337.5 mg/kg groups. The thyroid gland lesions observed were similar to those present in the 16-day study. Nine male rats receiving 168.8 mg/kg and ten male and seven female rats receiving.5 mg/kg had minimal but consistent changes in thyroid gland follicular cells. In the pituitary gland of 337.5 mg/kg males and females, the thyroid-stimulating hormone producing cells were enlarged and contained pale-staining cytoplasm and prominent Golgi complexes. Decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentration, similar to differences observed in the 16-day study, occurred in 337.5 mg/kg male rats; thyroid hormone concentrations were not affected in female rats. Sperm motility of all dosed groups of males was significantly lower than that of controls. Vaginal cytology parameters of dosed groups of females were similar to those of controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All mice survived to the end of the study. The final mean body weights of dosed male and female mice were similar to those of controls. The mean body weight gains of 1,350 and 2,700 mg/kg male mice were less than that of controls. No chemical-related clinical findings were noted in dosed male or female mice during the 13-week study. There was minimal evidence of a responsive anemia in mice in the 13-week study. The anemia was probably related to a methemoglobinemia. There were minimal decreases in thyroxine concentration in all dosed groups of male and female mice in the -week study. There were, however, no differences in triiodothyronine and thyroid-stimulating hormone concentrations between dosed and control animals. Absolute and relative liver weights of all groups of dosed male and female mice were significantly greater than those of controls. There were no chemical-related gross lesions. Microscopic evaluation of the liver revealed centrilobular hypertrophy in five 1,350 mg/kg and all 2,700 mg/kg male mice. The right cauda weight of the 1,350 mg/kg group and the right epididymis weights of all dose groups were significantly lower than those of controls. There was no evidence of chemical-related alteration in the vaginal cytology parameters of female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered 84, 168, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 105 weeks. Groups of 70 male and 60 female rats were administered the corn oil vehicle by gavage for up to 105 weeks. A stop-exposure group of 70 male rats was administered 337.5 mg/kg salicylazosulfapyridine in corn oil by gavage for 6 months, after which animals received the corn oil vehicle by gavage for the remainder of the 2-year study. Ten animals from the vehicle control male group and 10 animals from the 337.5 mg/kg stop-exposure group were evaluated at 6 months; animals from each core-study group were evaluated at 15 months. Survival, Body Weights, and Clinical Chemistry: Survival of 337.5 mg/kg male core-study rats was significantly lower than that of controls; survival of 84 and 168 mg/kg core-study males, all groups of dosed females, and the stop-exposure male group was similar to controls. Mean body weights of core-study males and stop-exposure males were similar to controls throughout the study. From week 45 to the end of the study, females in the 337.5 mg/kg group had mean body weights that were lower than those of controls. The serum thyroxine concentration in 337.5 mg/kg core-study males at study termination was minimally lower than that of controls; the serum thyroid-stimulating hormone, triiodothyronine, and reverse triiodothyronine concentrations of dosed males and females were similar to those of controls. Pathology Findings: Administration of salicylazosulfapyridine for 2 years was associated with transitional epithelial papilloma in the urinary bladder of male rats and may have been associated with transitional epithelial papilloma of the kidney and of the urinary bladder of female rats. Nonneoplastic effects in the urinary bladder and kidney of male and female rats and in the spleen of male rats were also observed. Dosed male and female rats had increased incidences of grossly and microscopically observed urinary bladder concretions (diagnosed grossly as calculi at necropsy); male and female rats that developed transitional epithelial papillomas of the urinary bladder had grossly observed concretions (calculi) in the urinary bladder at necropsy. The microscopic neoplastic and nonneoplastic urinary bladder and kidney effects observed in dosed male rats during the 2-year continuous study did not occur in dosed rats during the 2-year stop-exposure study, nor were there gross observations of concretions (calculi) at necropsy. The incidences of mononuclear cell leukemia in male and female rats were decreased. The thyroid gland hyperplasia seen in the -week study was not observed in the 2-year study, and there was no evidence of chemical-related thyroid gland follicular cell adenomas or carcinomas. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 104 weeks. Ten animals from each group were evaluated at 15 months. Survival, Body Weights,and Clinical Chemistry: Survival of all the dosed groups of male and female mice was similar to that of controls. Mean body weights of 675 and 1,350 mg/kg male and female mice were similar to controls throughout the study. From week 12 to the end of the study, 2,700 mg/kg male mice had mean body weights that were lower than those of controls. From week 14 to the end of the study, the 2,700 mg/kg female mice had mean body weights that were lower than those of controls. There were no chemical-related differences in triiodothyronine, reverse triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice at the 15-month evaluation. Pathology Findings: Exposure of mice to salicylazosulfapyridine in corn oil by gavage for 2 years was associated with increased incidences of hepatocellular neoplasms in males and females. Nonneoplastic effects in the liver and spleen were also observed in male and female mice. The incidences of forestomach squamous cell papilloma in females and forestomach hyperplasia in males and females were decreased. GENETIC TOXICOLOGY: Salicylazosulfapyridine was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro assays were performed with and without S9 metabolic activation enzymes. Results from in vivo mouse bone marrow chromo somal aberration tests were uniformly negative, while results of micronucleus assays performed on male or female mice exposed to salicylazosulfapyridine for periods ranging from 3 days to weeks were positive. Micronucleus tests in male mice for shorter exposure times (1 to 2 days) yielded negative or very weakly positive results. A three-treatment (72-hour exposure time) micronucleus test performed in male rats yielded equivocal results. Overall, results of these in vivo assays indicate that salicylazosulfa pyridine is capable of inducing chromosomal damage, possibly in the form of aneuploidy, in mouse bone marrow cells after multiple administrations. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of salicylazosulfapyridine in male and female F344/N rats based on increased incidences of neoplasms in the urinary tract. There was an increased incidence of transitional epithelial papilloma of the urinary bladder in males and a low incidence of rare transitional epithelial papillomas of the kidney and of the urinary bladder in females. There was clear evidence of carcinogenic activity of salicylazosulfapyridine in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Increased incidences of nonneoplastic lesions of the urinary bladder and kidney in male and female rats and of the spleen in male rats were observed. Increased incidences of nonneoplastic lesions of the liver and spleen in male and female mice were observed. Decreased incidences of mononuclear cell leukemia in male and female rats were related to salicylazosulfapyridine administration. Decreased incidences of forestomach squamous cell papilloma in female mice and forestomach hyperplasia in male and female mice were related to salicylazosulfapyridine administration. Synonyms: 2-Hydroxy-5-[[4-[2-(pyridinylamino)sulfonyl]phenyl]azo]benzoic acid; 5-[p- (2-pyridylsulfamoyl)phenylazo]salicylic acid; sulfasalazine; salazosulfapyridine; 5-[4-(2-pyridylsulfamoyl)phenylazo]-2-hydroxybenzoic acid; 4-(pyridyl-2-amidosulfonyl)-3'-carboxy-4'-hydroxyazobenzene; sulphasalazine Trade names: Azopyrin, Azulfidine, Benzosulfa, Colo-Pleon, Reupirin, Salazopyrin
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PMID:NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1258 19

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

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


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