Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A highly neuropathogenic retrovirus, NT40, was generated by serially passaging an infectious molecular clone of Friend murine leukemia virus, FB29, through F344 Fisher rats. NT40 induced severe neurological signs such as reflex abnormalities and ataxia within 4-6 weeks following neonatal inoculation. FB29 led to only very mild neurological dysfunctions with longer incubation periods. Pathological alterations were characterized by mild (FB29) to extensive (NT40) noninflammatory spongiform degeneration, mainly of brain-stem areas. Infectious center assays revealed that viral titers in brain tissues of NT40-infected rats were 100-fold higher than those of FB29-infected animals. Employing immunohistochemistry, in situ hybridization, and flow cytometry, NT40 was found to infect many endothelial cells of brain blood vessels and microglia, whereas FB29 infected only microglia and those to a lower extent. However, when isolated from adult diseased rats, microglial cells turned out in both cases to be nonproductively infected with either FB29 or NT40. Of peripheral organs, we found enhanced levels of NT40 in peritoneal macrophages but not in spleen, thymus, or serum when compared to FB29. Altogether these data suggest that an expanded cellular tropism within the CNS and elevated viral titers in macrophages and microglia correlated with enhancement of neuropathogenicity.
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PMID:Murine leukemia virus-induced neurodegeneration of rats: enhancement of neuropathogenicity correlates with enhanced viral tropism for macrophages, microglia, and brain vascular cells. 852 22

The Nijmegen breakage syndrome (NBS; MIM 251260), is an autosomal recessive disease characterized by microcephaly, growth retardation, immuno-deficiency and cancer predisposition. NBS cells show spontaneous chromosomal instability and hypersensitivity to ionizing radiation in combination with radioresistant DNA synthesis. At the cellular level, NBS has some features in common with ataxia teleangiectasia. In this study the murine Nbs1 gene was used for an expression study in mouse embryos at different developmental stages as well as in adult mice. A low level of expression is observed in all tissues. Highly specific expression was observed in organs with physiologic DNA double strand breakage (DSB), such as testis, thymus and spleen. Enhanced expression is also found at sites of high proliferative activity. These are the subventricular layer of the telencephalon and the diencephalon, the liver, lung, kidney and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum the postmitotic Purkinje cells are marked specifically. These expression patterns suggest that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development.
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PMID:Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. 1091 61

Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced. Microscopic lesions included degeneration of the seminiferous tubular cells, pyknosis or absence of germ cells, and hypospermia in the epididymis. Rats of the 600 ppm group had a slight decrease in thymic weight and a transient decrease in body weight. Results of the acute, 2-wk, and 13-wk inhalation studies indicate DMES concentrations of 1000 ppm and higher produce narcosis that rapidly disappears following exposure. Repeated exposure of rats to DMES at either 3000 ppm for 2 wk or 2000 ppm for 13 wk caused testicular atrophy and hypospermia in male rats. Female rats exposed to 2000 ppm for 13 wk had delayed estrous cycles. Toxicological effects in rats of the 600 ppm group were minimal and equivocal. The 160 ppm concentration was a no-observable-effect level (NOEL) for 13 wk of exposure to DMES.
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PMID:Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats. 1153 68

t-Butyl alcohol is widely used in the manufacture of perfumes and a variety of cosmetics. It is also used as a raw material in the production of isobutylene, which may be used to produce methyl tertiary butyl ether, a common gasoline additive, or to produce butyl elastomers used in the production of automobile tires. The National Cancer Institute nominated t-butyl alcohol to the NTP for study as a result of a review of chemicals found in drinking water. In addition to the high annual production and the potential for occupational exposure, there is also a potential for human exposure to t-butyl alcohol by the inhalation route from its use as an additive in unleaded gasoline. Therefore, toxicity studies of t-butyl alcohol were conducted in male and female F344/N rats and B6C3F1 mice by whole-body inhalation. Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, and histopathology. The genetic toxicity of t-butyl alcohol was assessed by testing the ability of the chemical to induce mutations in various strains of Salmonella typhimurium and L5178Y mouse lymphoma cells or sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, and by measuring the frequency of micronucleated erythrocytes in rat bone marrow and mouse peripheral blood. In the 18-day inhalation studies, groups of five male and five female rats and mice were exposed to t-butyl alcohol by inhalation at concentrations of 450, 900, 1,750, 3,500, and 7, 000 ppm for 6 hours per day, 5 days per week, for 12 exposure days. All rats and mice exposed to 7,000 ppm were killed moribund following a single 6-hour exposure. One 3,500 ppm male mouse died on day 3. Final mean body weights of 3,500 ppm male and female rats were significantly lower than those of the controls. Final mean body weights and body weight gains of all other exposed groups were similar to those of the controls. In animals exposed to 3.500 ppm, the thymus weights of male and female rats and female mice were less than those of the controls. The liver weights of male and female mice exposed to 3,500 ppm were greater than those of the controls. No grss or microscopic lesion were present in rats or mice. In the 13-week inhalation studies, groups of 10 male and 10 female rats and mice were exposed to t-butyl alcohol at concentrations of 0, 135, 270, 540, 1,080, and 2,100 ppm for 6 hours per day, 5 days per week, for 13 weeks. One 2,100 ppm and five 1,080 ppm male mice died before the end of the studies. The final mean body weight of 2,100 ppm female mice and the mean body weight gains of 1,080 and 2,100 ppm female mice were significantly lower than those of the controls. Clinical findings of toxicity in the 1,080 ppm male mice died during the studies included rough coats and emaciated appearance, hypoactivity, and prostration. Minimal decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts occurred in the 1,080 and 2,100 ppm male rats at week 13. Hemoglobin concentrations and/or hematocrit values were also minimally decreased in male rats in the lower exposure groups. At week 13, a minimal decrease in urine pH occurred in the 1,080 ppm female and 2,100 ppm male and female rats. Neutrophilia occurred in the 2,100 ppm male mice. Organ weight differences in exposed rats included increased absolute and relative kidney weights of 1,080 ppm males and 2,100 ppm males and females and increased relative liver weights of 1,080 and 2,100 ppm females. There were no treatment-related gross findings in male or female rats or mice; no microscopic lesion occurred in female rats or male or female mice that survived to the end of the study. In male rats, there was an exposure concentration-related increase in the severity of chronic nephropathy. Splenic lymphoid depletion was present in male mice that died during the studies; this lesion was presumed to be secondary to stress. t-butyl alcohol produced no adverse effects on reproductive parameters in male or female rats or mice. The results of all tests of t-butyl alcohol for induction of genetic damage in vitro and in vivo were negative. In vitro, t-butyl alcohol was negative in Salmonella typhimurium and mouse lymphoma cell mutation test, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro studies were conducted with and without metabolic activation (S9). In vivo, no increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from mice administered t-butyl alcohol in drinking water for 13 weeks. Also, induction or micronucleated erythrocytes was noted in bone marrow cells of rats administered t-butyl alcohol by intraperitoneal injection. In summary, inhalation exposure of rats and mice to t-butyl alcohol resulted in deaths following a single 7,000 ppm exposure and clinical findings of alcohol toxicity (hyper- and hypoactivity, ataxia) at concentrations of 900 ppm and greater in rats and 1,750 ppm and greater in mice. In 13-week studies at concentrations up to 2,100 ppm, only one death (that of a 2,100 ppm mouse) was attributed to chemical exposure. The most notable evidence of toxicity at the end of 13 weeks was limited to males and consisted of increased kidney weights, which correlated microscopically to increased severity of chronic nephropathy. Reproductive parameters in male and female rats and mice were unaffected after 13 weeks of exposure, and the results of all tests for genetic toxicity were negative.
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PMID:NTP technical report on toxicity studies of t-butyl alcohol (CAS No. 75-65-0). Administered by inhalation to F344/N rats and B6C3F1 mice. 1180 4

Methacrylonitrile is an aliphatic nitrile used extensively in the preparation of homo- and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, esters, and other nitriles. This aliphatic nitrile is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. Methacrylonitrile was nominated for toxicity and carcinogenicity testing by the National Cancer Institute due to its high production volume and extensive use, the lack of chronic or carcinogenicity data, and its structural resemblance to the known rat carcinogen acrylonitrile. The current 13-week studies were conducted as part of an overall effort by the NTP to assess the toxicity and carcinogenicity of methacrylonitrile. During the 13-week studies, groups of 20 male and 20 female F344/N rats were administered 0, 7.5, 15, 30, 60, or 120 mg methacrylonitrile/kg body weight in deionized, purified water by gavage. Groups of 20 male and 20 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg/kg methacrylonitrile. Ten male and ten female rats and mice from each group were evaluated on day 32. The results of these studies clearly revealed that male rats are more sensitive than females to methacrylonitrile treatment. In the rat study, 19 males and one female administered 120 mg/kg and two males administered 60 mg/kg died during the first week of the study. Males in the 60 mg/kg group at the 32-day interim evaluation and at 13 weeks and females in the 120 mg/kg group at 13 weeks had significantly lower final mean body weights and body weight gains than did the vehicle controls; the surviving male in the 120 mg/kg group also weighed less than the controls at the 32-day interim evaluation. Clinical findings of toxicity were dose dependent and included lethargy, lacrimation, tremors, convulsions, ataxia, and abnormal breathing. There was hematologic evidence indicating that administration of methacrylonitrile induced minimal, normocytic, normochromic anemia. At the 32-day interim evaluation, a minimal dose-related anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in male and female rats. The anemia ameliorated by week 13. Administration of methacrylonitrile resulted in dose-related increases in serum thiocyanate and blood cyanide concentrations of male and female rats. These changes were expected and would be consistent with the in vivo metabolism of methacrylonitrile to cyanide. Blood cyanide concentrations were generally higher in males than in females, which may explain the higher sensitivity of males to the lethal effect of methacrylonitrile. There was also biochemical evidence of increased hepatocellular leakage and/or altered function in dosed male rats, suggesting that the liver may be a target organ for toxic effects of methacrylonitrile. Minimal, but significant, decreases in absolute right kidney and thymus weights (32-day interim evaluation) and increases in liver and stomach weights (week 13) occurred in male rats that received 60 mg/kg compared to the vehicle controls. In female rats, stomach weights of the 60 and 120 mg/kg groups were significantly greater and thymus weights of the 120 mg/kg group were significantly less than those of the controls on day 32 and at week 13; liver weights were also significantly greater in females in the 120 mg/kg group than in the vehicle controls on day 32. Male and female rats administered 60 mg/kg and females administered 120 mg/kg had significantly greater incidences of metaplasia of the nasal olfactory epithelium on day 32 and at the end of the study than did the vehicle controls; incidences of olfactory epithelial necrosis were also significantly greater in females in the 60 and 120 mg/kg groups than in the vehicle controls on day 32. Incidence and/or severity increased with increasing dose in females; however, the mortality in male rats administered 120 mg/kg made it difficult to assess the dose-response relationship in males. The no-observed-adverse-effect level for the nasal cavity of rats was 30 mg/kg. Female rats administered 60 or 120 mg/kg methacrylonitrile had significantly longer estrous cycles than did the vehicle controls. Females in the 60 mg/kg group spent more time in diestrus than the vehicle controls. One male and one female mouse in the 12 mg/kg groups died early. Methacrylonitrile administration caused no significant differences in final mean body weights or body weight gains. Clinical findings included lethargy, tremors, ataxia, convulsions, and abnormal breathing. At the 32-day interim evaluation, stomach weights of males administered 3 mg/kg or greater were significantly greater and thymus weights of males in the 12 mg/kg group were significantly less than those of the vehicle controls. At week 13, however, the stomach weights of only males in the 12 mg/kg group were increased relative to the vehicle controls. No treatment-related histopathologic lesions occurred in mice. Methacrylonitrile did not induce mutations in any of several strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with methacrylonitrile in male rats and mice were also negative. In summary, gavage administration of methacrylonitrile to rats and mice resulted in dose-dependent lethargy, tremors, lacrimation, convulsions, and abnormal breathing. However, these effects were more pronounced in rats than mice; these differences may be attributed to the higher doses of methacrylonitrile administered to rats. Body weight gain and survival data of rats demonstrated that males are more sensitive to methacrylonitrile dosing than females. There is an apparent correlation between blood cyanide concentrations and survival rates, with males having greater cyanide concentrations and lower survival rates than female rats administered methacrylonitrile. Microscopically, the only target of methacrylonitrile toxicity was the olfactory epithelium of the nasal cavity. Necrotic and metaplastic effects were induced in male and female rats that received 60 or 120 mg/kg per day. No similar lesions were observed in mice administered methacrylonitrile. The no-observed-adverse-effect level for olfactory epithelial lesions in male and female rats administered methacrylonitrile for 13 weeks was 30 mg/kg per day. No clear chemical-related effects were observed in male or female mice administered methacrylonitrile for 13 weeks by gavage at doses up to 12 mg/kg per day.
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PMID:NTP technical report on the toxicity studies of methacrylonitrile (CAS No. 126-98-7). Administered by gavage to F344/N rats and B6C3F1 mice. 1180 6

Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)
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PMID:Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells. 1196 80

The clinical features and laboratory findings of 18 children with various primary immune deficiencies and their immunologic diagnosis have been discussed. In 3 patients of ataxia telangiectasis human foetal thymus transplantations have been performed with some success.
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PMID:Primary immune disorders in children and their diagnosis. 1205 80

Approximately 5,000 to 80,000 of the US service personnel involved in the Persian Gulf War have complained of a variety of nonspecific symptoms since their return in 1991. These symptoms have been collectively labeled Gulf War Illness and include muscle fatigue, general malaise, myalgia, impaired cognition, ataxia, headaches, fever, joint pain, skin rash, gastrointestinal disturbances, sleep disturbances, and respiratory difficulties. Exposures of military and service personnel were diverse and included the prescribed anti-nerve gas agent pyridostigmine bromide (PYR), N.N-diethyl-m-toluamide (DEET) insect repellent, and environmental exposures to jet fuel. Thus, studies in our laboratory were undertaken to determine if concurrent exposure to these agents, singly or in combination, would contribute to significant alterations in immunological function and disease susceptibility. To assess immune status, eight-week old B6C3F1 female mice were exposed for 14 days to single compounds or tertiary mixtures of 15.5 mg/kg DEET, 2 mg/kg PYR, and 500 mg/kg JP-8 (termed low dose), or 31 mg/kg DEET, 5 mg/kg PYR, and 1,000 mg/kg JP-8 (termed high dose). Immunosuppression was assessed 24 h after the last exposure. No remarkable alterations were evident in hematological parameters, spleen and thymus organ weight and total cellularity, natural killer (NK) cell activity, cytotoxic T-cell activity, or mitogen-induced lymphocyte proliferation after exposure to either single or tertiary mixtures at low or high doses. A few changes in CD4/CD8 flow cytometric lymphocyte subpopulations were detected after exposure to the tertiary mixture at the high dose. Delayed type hypersensitivity (DTH) was decreased by 88% after exposure to the high-dose mixture, and suppression of antibody-specific IgM immune responses (plaque-forming cell, PFC) occurred after exposure to all single and tertiary mixtures at both dose levels. In the PFC response, antagonism was apparent in the mixture, while coexposure to these agents resulted in a synergistic effect in the DTH response. Susceptibility to B16F10 tumor or Listeria monocytogenes challenge was not affected after single or tertiary exposures. These data suggest that combined exposure to DEET, PYR, and JP-8 does not profoundly alter many immunological endpoints, but does selectively target functional endpoints such as the PFC and DTH response. This should be considered when assessing human health risks in the military environment.
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PMID:Evaluation of immunotoxicity induced by single or concurrent exposure to N,N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel. 1253 64

Tetrahydrofuran is used as a reaction medium for Grignard and metal hydride reactions; in the synthesis of butyrolactone, succinic acid, and 1,4-butanediol diacelate; in the fabrication of articles for packaging, transporting, and storing of foods; as a solvent for dyes and lacquers; and as a chemical intermediate in polymerization solvent for fat oils, unvulcanized rubber, resins, and plastics. Tetrahydrofuran is also an indirect food additive when it is in contact with the surface of articles intended for use in food processing. Tetrahydrofuran was nominated for study because of the potential for occupational exposure in humans. Male and female F344/N rats and B6C3F1 mice were exposed to tetrahydrofuran (approximately 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse bone marrow cells, and mouse peripheral blood cells erythrocites. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0 (chamber control), 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. Final mean body weights and mean body weight gains of exposed groups of male and female rats were similar to those of the chamber controls. Immediately after exposure, male and female rats in the 5,000 ppm groups exhibited ataxia. Hematologic and serum chemistry changes were minimal, with most values falling within physiologic ranges. Absolute and relative thymus and spleen weights of male and female rats exposed to 5,000 ppm were significantly less than those of the chamber controls. Absolute and relative liver weights of female rats exposed to 5,000 ppm were significantly greater than those of the chamber controls. Increased incidences of minimal to mild hyperplasia of the forestomach were observed in male and female rats exposed to 5,000 ppm. Minimal suppurative inflammation was associated with forestomach hyperplasia in two male rats and four female rats exposed to 5,000 ppm. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. Two male mice exposed to 5,000 ppm died during weeks 2 and 8 of the study; one male mouse from the 5,000 ppm group was killed in a moribund state during week 4. All female mice survived until the end of the study. The final mean body weights and mean body weight gains of all exposed groups of male mice were similar to those of the chamber controls. The final mean body weight and mean body weight gain of the 5,000 ppm female mice were significantly greater than those of the chamber controls. Male and female mice exposed to 1,800 or 5,000 ppm were observed in a state of narcosis (described by stupor) during exposure periods. Mice exposed to 1,800 ppm were fully awake and alert immediately after exposure; however, mice exposed to 5,000 ppm required up to 2 hours for recovery. Absolute and relative liver weights of male mice exposed to 600 ppm or greater and of female mice exposed to 1800 or 5,000 ppm were significantly greater than those of the chamber controls. Absolute and relative thymus weights of male mice exposed to 600, 1,800, or 5,000 ppm were significantly less than those of the chamber controls. The incidences of minimal to mild centrilobular cytomegaly of the liver in male and female mice exposed to 5,000 ppm were significantly greater than those in the chamber controls. The adrenal glands of all female mice exposed to 5,000 ppm had mild degeneration of the X-zone of the innermost cortex. Uterine atrophy was observed in all female mice exposed to 5,000 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings Survival and mean body weights of male and femand female rats exposed to tetrahydrofuran were similar to those of the chamber controls. Pathology Findings: The incidences of renal tubule epithelial adenoma or carcinoma (combined) in exposed males occurred with a positive trend, and the incidences in 600 and 1,800 ppm males exceeded the historical range for chamber controls in 2-year NTP inhalation studies. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings After week 36, the survival of male mice exposed to 1,800 ppm was significantly less than that of the chamber controls. Mean body weights of male and female mice exposed to tetrahydrofuran were similar to those of the chamber controls throughout the study. Male mice exposed to 1,800 ppm were observed to be in a state of narcosis during and up to 1 hour after the exposure periods. Pathology Findings: The incidences andmultiplicity of hepatocellular neoplasms were significantly greater in female mice exposed to 1,800 ppm than in the chamber controls. The incidence of nephropathy in 200 ppm male mice was significantly greater than that in the chamber control group. Male mice exposed to 1,800 ppm had significantly greater incidences of nonneoplastic lesions of the urogenital tract than did the chamber controls. The incidences of inflammation of the penis and urethra and necrosis of the urethra in 1,800 ppm males were slightly greater than those in the chamber controls; these may have been secondary effects of ascending urinary tract infection. GENETIC TOXICOLOGY: Tetrahydrofuran showed little evidence of mutagenic activity in a variety of in vitro and in vivo assays. It was not mutagenic in Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation from induced liver S9 enzymes. No increase in sex-linked recessive lethal mutations was detected in germ cells of male D. melanogaster exposed to tetrahydrofuran by feeding or injection. Results of in vivo assays for induction of chromosomal aberrations and sister chromatid exchanges in mouse bone marrow cells were negative. A micronucleus test in male and female mice exposed to tetrahydrofuran for 14 weeks showed no significant increases in the frequency of micronucleated erythrocytes in peripheral blood of female mice, but in male mice, analysis of micronucleated normochromatic erythrocyte levels revealed a small increase above baseline that was concluded to be equivocal. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of tetrahydrofuran in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of tetrahydrofuran in female F344/N rats exposed to 200, 600, or 1,800 ppm or male B6C3F1 mice exposed to 200, 600, or 1,800 ppm. There was clear evidence of carcinogenic activity of tetrahydrofuran in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Synonyms: Butylene oxide; cyclotetramethylene oxide; diethylene oxide; 1,4-epoxybutane; furanidine; hydrofuran; oxacyclopentane; oxolane; tetramethylene oxide
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PMID:NTP Toxicology and Carcinogenesis Studies of Tetrahydrofuran (CAS No. 109-99-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 88

Acetonitrile is used primarily as a solvent in extractive distillation and crystallization of pharmaceutical and agricultural products and as a catalyst in chemical reactions. It was nominated for testing by the National Cancer Institute due to its presence in drinking water supplies and the environment, due to lack of information on the carcinogenicity of alkyl cyanides, and because of widespread worker exposure. Male and female F344/N rats and B6C3F1 mice were exposed to acetonitrile (at least 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood of B6C3F1 mice exposed to acetonitrile for 13 weeks. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. Six male and three female rats that received 1,600 ppm and one male that received 800 ppm died during the study. At exposure concentrations up to and including 800 ppm, the final mean body weights and body weight gains were generally similar to those of the controls. At 1,600 ppm, body weight gain was lower and the final mean body weights of both males and females were significantly lower than those of the controls. Hypoactivity and ruffled fur were observed during the first week of the study in males receiving 800 ppm and males and females receiving 1,600 ppm. Additional clinical findings in 1,600 ppm males that died during week 1 were ataxia, abnormal posture, and clonic convulsions. Clinical pathology findings included nonresponsive, normocytic, normochromic anemia in 1,600 ppm males and females and in 800 ppm females, and decreased triiodothyronine (T3) concentrations in 1,600 ppm females. Absolute and relative thymus weights were significantly lower than those of the controls in the 800 and 1,600 ppm males and females. Females exposed to 1,600 ppm had significantly greater absolute and relative heart, kidney, and liver weights than those of the controls. There were no clear exposure-related histopathologic effects, although pulmonary congestion and edema and hemorrhage in the lung and brain were seen in some rats that died early. These lesions are consistent with cyanide-induced anoxia. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 100, 200, 400, 800, or 1,600 ppm (equivalent to 0, 168, 335, 670, 1,340, or 2,681 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 13 weeks. All mice exposed to 1,600 ppm died during the first 3 weeks of the study. In addition, one 400 ppm female and one male and four females from the 800 ppm groups also died before the end of the study. Body weight gains were similar to those of controls for all surviving groups of mice except the 800 ppm males, for which the final mean body weight was slightly lower than that of the controls. Clinical findings observed during the first week in 800 and 1,600 ppm mice were hypoactivity and a hunched, rigid posture. In males that received 200 ppm and above, absolute liver weights were greater than that of the controls and relative liver weights were greater in all exposed groups. In 800 ppm females, the absolute liver weight was greater than that of the controls and relative liver weights of females that received 400 ppm and above were greater than that of the controls. Lesions clearly associated with acetonitrile exposure were observed in the stomach, predominantly the forestomach, of males that received 400 ppm and above and of females that received 200 ppm and above. Histologically, these focal or multifocal pale to dark raised lesions consisted of areas of focal epithelial hyperplasia and ulceration, sometimes associated with hemosiderin deposition. An increased incidence of cytoplasmic vacuolation occurred in the liver of males and females exposed to 400 or 800 ppm. A lack of fatty degenerative change was observed inrved in the X-zone of the adrenal cortex of 800 and 1,600 ppm female mice. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of acetonitrile were based on reduced survival of 800 ppm males and 1,600 ppm males and females in the 13-week study. Groups of up to 56 male and 56 female rats were exposed to 0, 100, 200, or 400 ppm (equivalent to 0, 168, 335, or 670 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Eight male and eight female rats from each exposure group were evaluated at 15 months for histopathology and hematology parameters. Survival, Body Weights, Clinical Findings, and Hematology: Two-year survival, mean body weights, organ weights, behavior, general health, and appearance of exposed male and female rats were similar to those of the controls. The hematologic effects observed were minor and of no biological significance. Pathology Findings: The incidences of hepatocellular adenoma (3/48), hepatocellular carcinoma (3/48), and hepatocellular adenoma or carcinoma (combined; 5/48) were greater in male rats exposed to 400 ppm than in the controls (one carcinoma). The incidences of hepatocellular adenoma and hepatocellular carcinoma were within the range of historical controls. However, the incidence of hepatocellular adenoma or carcinoma (combined) slightly exceeded the range of historical controls (2%-8%). In addition, the incidences of basophilic, eosinophilic, and mixed cell foci in 400 ppm males were marginally greater than in controls, suggesting hepatotoxicity of acetonitrile. There were no exposure-related liver lesions in female rats. 2-YEAR STUDY IN MICE: The exposure concentrations selected for the 2-year study were based on reduced survival and gross and histopathologic lesions in 400, 800, and 1,600 ppm groups of male and female mice in the 13-week study. Groups of 60 male and 60 female mice were exposed to 0, 50, 100, or 200 ppm (equivalent to 0, 84, 168, or 335 mg/m(3)) acetonitrile by inhalation for 6 hours per day, 5 days per week for 2 years. Ten male and 10 female mice from each exposure group were evaluated at 15 months for histopathology. Survival, Body Weights, and Clinical Findings: Two-year survival of exposed male and female mice was similar to that of the controls, except that the survival of male mice in the 200 ppm group was significantly greater than that of the controls. Mean body weights and organ weights of exposed groups of male and female mice were similar to those of the controls, and no clinical observations in any group were clearly related to acetonitrile exposure. Pathology Findings: There were no increases in the incidences of neoplasms that were considered related to acetonitrile exposure in mice. The incidence of squamous hyperplasia of the epithelium of the forestomach was significantly increased at 15 months in 200 ppm females. At 2 years, the increased incidence of this lesion was dose related in all exposed groups of males and females. GENETIC TOXICOLOGY: Acetonitrile was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, TA1535, or TA1537, with or without S9 metabolic activation. In cultured Chinese hamster ovary cells, acetonitrile produced a weakly positive response in the sister chromatid exchange test without, but not with, S9. A small increase in chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with acetonitrile in the presence, but not in the absence, of S9. A significant increase in micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male mice treated with acetonitrile for 13 weeks; the frequency of micronucleated erythrocytes in female mice was not affected by exposure to acetonitrile. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of acetonitrile in male F344/N rats based on marginally increased incidences of hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm. There was no evidence of carcinogenic activity of acetonitrile in male or female B6C3F1 mice exposed to 50, 100, or 200 ppm. Exposure to acetonitrile by inhalation resulted in increased incidences of hepatic basophilic foci in male rats and of squamous hyperplasia of the forestomach in male and female mice. Synonyms: Cyanomethane, ethanenitrile, ethyl nitrile, methanecarbonitrile, methyl cyanide, nitrile of acetic acid
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PMID:NTP Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 75-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1259 28


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