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)

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan
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PMID:NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1257 87

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

p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an intermediate in the manufacture of pesticides, dyes, and industrial solvents. Groups of male and female F344/N rats and B6C3F1 mice were exposed to p-nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for toxicity and carcinogenicity studies. Genetic toxicology studies were conducted in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary cells, and in studies of erythrocyte micronucleus formation in mice in the 13-week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. All rats survived until the end of the study. Male and female rats given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000, 20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%, and 65% that of the controls. There were no clinical findings that were characteristic of organ-specific toxicity. Absolute and relative spleen weights were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm. There were decreases in erythrocyte count and hemoglobin and hematocrit values and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin concentration that were most pronounced in the 20,000 and 40,000 ppm groups. Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000 ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of the thymus in males and atrophy of the ovary, bone marrow, and thymus in females. 14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. Three males and two females given 40,000 ppm died during the study. All other animals survived until the end of the study. Male mice given 20,000 and 40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of 20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were significantly lower than those of the controls. There were no clinical findings related to organ-specific toxicity although lethargy and ataxia were observed in 40,000 ppm mice. Relative liver weights were significantly increased in 20,000 and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000 ppm females were reduced. No significant differences in hematology parameters occurred in exposed mice. Testicular degeneration was observed in three 20,000 ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in 40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660 mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived until the end of the study. Mean body weight gains and final mean body weights were significantly less than those of the controls in 2,500, 5,000, and 10,000 ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings related to organ-specific toxicity. Differences in spleen weights and hematology parameters characteristic of regenerative anemia were observed in males and females, primarily in groups given 10,000 ppm. The absolute and relative spleen weights were significantly increased in 10,000 ppm males and females and the relative spleen weights were significantly increased in 5,000 ppm males hts were significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz bodies, and reticulocyte counts were increased and erythrocyte counts, hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females. Congestion, pigmentation, and accumulation of macrophages in the spleen and pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males. Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A yellowish brown pigment (hemosiderin) in the spleen and kidney was associated with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p-nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or 20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460, 970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the study, except one 1,250 ppm female that was killed accidentally. Final mean body weights and mean body weight gains of all exposed males and of 5,000, 10,000, and 20,000 ppm females were significantly lower than those of the controls. No clinical findings or differences in organ weights or histopathology related to organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500 ppm males were similar to that of the controls. Two-year survival of 5,000 ppm males was marginally greater than that of the controls and was attributed in part to a decrease in the severity of nephropathy and a decrease in the incidence of mononuclear cell leukemia. Survival of exposed females was similar to that of the controls. Mean body weights of 5,000 ppm males were 2% to 8% lower than those of the controls through week 80. Final mean body weights of exposed males were similar to that of the controls. Mean body weights of 5,000 ppm females were 2% to 9% lower than those of the controls during the first year of the study and were 10% to 16% lower during the second year of the study. Final mean body weights of exposed females were 97% (1,250 ppm), 92% (2;500 ppm), and 84% (5,000 ppm) that of the controls. Feed consumption by exposed males and females was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 50, 100, or 210 mg/kg body weight per day to males and 60, 125, or 250 mg/kg per day to females. There were no clinical findings attributable to organ-specific toxicity. Pathology Findings: There were increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The incidences of clitoral gland adenoma or carcinoma (combined) in the exposed groups (29% to 31%) exceeded the historical control mean incidence (11%) and range (2% to 21%) in female F344/N rats in recent 2-year NTP feed studies. The increased incidences of clitoral gland neoplasms were considered to be some evidence of carcinogenic activity in female rats exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral gland in exposed females were marginally lower than that of the controls (10/50, 6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of nephropathy in male rats. Male rat kidneys were examined using both single and step-section analyses, and the incidences of renal tubule neoplasms were not statistically greater than those of the controls. Mild hyaline droplet accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in the 13-week study, but this effect was not severe enough to lead to a chemical-related neoplastic response in the 2-year study as has been observed with other chemicals. At the 15-month interim evaluation, hematologic parameters characteristic of a mild regenerative anemia and significant differences in spleen weights were noted in 5,000 ppm females. These differences included decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen weights, and hemosiderin accumulation in splenic macrophages. At 2 years, significant decreases in the incidences of mononuclear cell leukemia were observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50, 26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this decrease is unknown, decreases in the incidence of mononuclear cell leukemia have also been observed in 2year studies with other amine/nitro compounds. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice were similar to those of the controls. Mean body weights of 5,000 ppm males were 6% to 12% lower than those of the controls after week 17, and mean body weights of 5,000 ppm females were 12% to 24% lower than those of the controls after week 16. The final mean body weight of 5,000 ppm females was 19% less than that of the controls; final mean body weights of males were similar to that of the controls. Feed consumption by exposed mice was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of organ-specific toxicity. No chemical-related effects on hematology parameters were noted at the 15-month interim evaluation. Pathology Findings: There were no increases or decreases in neoplasms in male or female mice that were considered to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, results of both tests were negative. In vivo, no increase in micronuclei was observed in peripheral blood erythrocytes of male or female mice administered p-nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of p-nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female F344/N rats based on increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in the incidences of mononuclear cell leukemia in exposed male and female rats. p-Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4-Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p-carboxynitrobenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 21

The paper aims to present the case of a progressive and unilateral cranial polyneuropathy due to perineural spread of cutaneous squamous cell carcinoma. This is a case of a 73 year old man with a history of squamous cell carcinoma in the right temporal region that was removed in 1992. In May 2000 he first presented pain and numbness in the distribution of the first branch of right trigeminal nerve and weakness of the ipsilateral frontal muscle. Later on he presented right ophthalmoplegia, and damage of lower cranial nerves, leading to dysphagia and respiratory distress. He was admitted in March 2001 for a gastrostomy for feeding, when ataxia and recurrence of the right temporal lesion ensued. After three examinations with MRI, the fourth study showed meningeal carcinomatous and a metastatic lesion in the brainstem. Histopathologic examination demonstrated dermal and perineural invasion by squamous cell carcinoma. The necropsy also showed meningeal, perineural and endoneural infiltration of atypical epidermal cells and a pons mass composed of the same cells. We conclude that the perineural spread of the cutaneous carcinoma is an exceptional cause of cranial neuropathy, however it must be ruled out in patients with progressive and unilateral cranial neuropathy. In these cases, when no radiological abnormalities are noted, a biopsy may be performed on the peripheral branches of the cranial nerve to confirm the diagnosis.
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PMID:[Progressive cranial neuropathy due to perineural spread of a facial squamous cell carcinoma]. 1261 Jul 61

Coumarin is the basic structure of numerous naturally occurring compounds with important and diverse physiological activities. More than a thousand coumarin derivatives have been described, varying from simple coumarins containing alkyl and hydroxyl side chains to complex coumarins with benzoyl, furanoyl, pyranoyl, or alkylphosphorothionyl substituents. Coumarin and 3,4-dihydrocoumarin were nominated by the Food and Drug Administration and the National Cancer Institute for study because of the widespread use of coumarin in perfumes, cosmetics, and other products as a fragrance, continued interest in coumarin compounds as flavor-enhancing agents for foods, and the interest in structure-activity relationships of this important group of compounds. Coumarin is believed to be metabolized to a 3,4-epoxide intermediate, which may be responsible for its toxic effects, while 3,4-dihydrocoumarin, which lacks the 3,4-double bond, is not considered likely to form an epoxide intermediate. Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and B6C3F1 mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received coumarin in corn oil by gavage at doses of 0, 25, 50, 100, 200, or 400 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All female rats and four male rats receiving 400 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female rats were similar to those of the controls. There were no clinical signs of organ-specific toxicity, and there was no evidence of impaired blood coagulation from measurements of capillary clotting time or prothrombin and activated partial thromboplastin time. 16-DAY STUDY IN MICE: Groups of five male and five female mice received coumarin in corn oil by gavage at doses of 0, 40, 75, 150, 300, or 600 mg per kg body weight, 5 days a week for a total of 12 doses in a 16-day period. All mice receiving 600 mg/kg, two male mice receiving 300 mg/kg, and one male mouse receiving 75 mg/kg died. The mean body weight gains and final mean body weights of surviving dosed male and female mice were similar to those of the controls. Clinical findings of inactivity, excessive lacrimation, piloerection, bradypnea, ptosis, or ataxia were observed in some mice from the 300 and 600 mg/kg groups within the first several hours after dosing. Capillary clotting time and platelet counts of dosed mice were similar to those of controls. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received coumarin in corn oil by gavage at doses of 0,19, 38, 75,150, or 300 mg per kg body weight. Three male and three female rats receiving 300 mg/kg died. The mean body weight gains and final mean body weights of male rats that received 150 and 300 mg/kg were significantly lower than those of the controls. There were no clinical signs related to specific organ toxicity. Male and female rats receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin, and dose-related increases in erythrocyte counts. Serum levels of total bilirubin and one or more cytoplasmic enzymes including alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and/or sorbitol dehydrogenase in males and females receiving 300 mg/kg were higher than those of controls. The absolute and relative liver weights of male and female rats that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular degeneration and necrosis, chronic active inflammation, and bile duct hyperplasia were observed in the liver of rats receiving 150 or 300 mg/kg. The high dose selected for the 2-year study was 100 mg/kg, which was just below the level at which mortality, lower final mean body weiody weights, and treatment-related liver lesions were observed in the 13-week study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received coumarin in corn oil by gavage at doses of 0, 19, 38, 75, 150, or 300 mg per kg body weight. Two male mice receiving 300 mg/kg died. The mean body weight gain and final mean body weight of surviving male mice that received 300 mg/kg were significantly lower than those of the controls. No clinical signs of toxicity were observed. Male and female mice receiving coumarin exhibited dose-related decreases in mean erythrocyte volume and mean erythrocyte hemoglobin. The absolute and relative liver weights of males and females that received 150 and 300 mg/kg were significantly greater than those of the controls. Centrilobular hepatocellular hypertrophy was observed in male and female mice receiving 300 mg/kg. The high dose selected for the 2-year study was 200 mg/kg, which was just below the level at which mortality and liver lesions were observed in the 13-week study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered coumarin in corn oil by gavage at doses of 0, 25, 50, or 100 mg per kg body weight. After 15 months, 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: None of the male rats receiving 100 mg/kg and only two males receiving 50 mg/kg survived until the end of the study (vehicle control, 28/50; 25 mg/kg, 9/50; 50 mg/kg, 2/51; 100 mg/kg, 0/50). Survival of dosed female rats was similar to that of the controls (29/50, 38/50, 36/50, 30/50). The reduced survival in dosed male rats was primarily attributed to chemical-related exacerbation of spontaneously occurring renal disease. Final mean body weights of female rats that received 100 mg/kg and all dosed groups of male rats were lower than those of the controls. There were no clinical signs of toxicity in rats, other than nonspecific signs relating to debilitation as a result of renal or other spontaneous disease. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the values for one or more hematologic parameters including mean erythrocyte volume, mean erythrocyte hemoglobin in 50 and 100 mg/kg rats, and hematocrit or hemoglobin in 100 mg/kg rats were significantly lower than those of controls. Activated partial thromboplastin times were also significantly lower in 50 and 100 mg/kg males, while platelet counts were significantly higher. Activities of alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in 50 and 100 mg/kg male and 100 mg/kg female rats were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: The principal lesions associated with the administration of coumarin to rats for up to 2 years occurred in the liver, kidney, and forestomach. While the hepatic lesions were seen in all groups of males, they occurred only in the 50 and 100 mg/kg females. The lesions consisted of a spectrum of changes including hepatocellular necrosis, fibrosis, cytologic alteration, and increased severity of bile duct hyperplasia. The incidences of hepatocellular neoplasms were not increased in dosed rats. There was a chemical-related increase in the average severity of nephropathy in all groups of dosed male and female rats. There were corresponding increased incidences of parathyroid gland hyperplasia in all groups of dosed males, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, a low incidence of renal adenomas was seen in all groups of males and in 100 mg/kg females (males: vehicle control, 1/49; 25 mg/kg, 2/50; 50 mg/kg, 2/51; 100 mg/kg, 1/50; females: 0/49, 0/50, 0/50, 2/49). An evaluation of step sections identified additional individuals with renal tubule focal hyperplasia (males: 2/49, 12/50, 10/51, 6/50; females: 1/49, 0/50, 4/50, 2/49) and adenoma (males: 0/49, 4/50, 5/51, 4/50; females: 0/49, 0/50, 1/50,1/49) in the dosed groups. The incidences of forestomach ulcers in all groups of dosed male rats and in 100 mg/kg female rats were significantly greater than those of the controls (males: 7/48, 24/50, 35/51, 34/50; females: 1/48, 1/49, 6/50, 9/48). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 100 mg/kg coumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle during the 15-month recovery period. Similarly, a group of 30 male rats received 100 mg/kg coumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil during the 9-month recovery period. A group of 20 vehicle control male rats were necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. While chemical-related hepatic lesions were seen at both the 9- and 15-month interim evaluations, the incidences and severities of these lesions following the recovery period were generally similar to controls. Thus, the hepatic lesions produced by 9 or 15 months of exposure were reversible. In contrast to the liver lesions, the severity of nephropathy in male rats following the recovery period was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This is not unexpected, since nephropathy is a progressive degenerative disease that naturally increases in severity with age. The incidence of renal tubule hyperplasia in the 15-month stop-exposure group (dosed for 15 months followed by the recovery period) and the incidence of renal tubule adenoma in the 9-month stop-exposure group were significantly greater than those of the control group. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered coumarin in corn oil by gavage at doses of 0, 50, 100, or 200 mg per kg body weight for up to 2 years. After 15 months, 19 or 20 mice from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival of dosed male and female mice was similar to that of the controls (males: vehicle control, 43/50; 50 mg/kg, 47/50; 100 mg/kg, 42/50; 200 mg/kg, 37/51; females: 33/50, 40/50, 42/51, 28/51). The mean body weights of 200 mg/kg male and female mice were lower than those of controls throughout much of the study. There were no clinical findings related to chemical administration. Hematology and Clinical Chemistry: Mean erythrocyte volume, mean erythrocyte hemoglobin, and hematocrit of 200 mg/kg males and mean erythrocyte volume of 200 mg/kg females were significantly lower than those of the controls. Blood platelet counts of 200 mg/kg males and females were significantly higher than those of controls. There were no biologically significant differences in enzyme activities between dosed and control mice. Pathology Findings: The principal toxic lesions associated with the administration of coumarin to mice occurred in the liver. The incidences of centrilobular hypertrophy in 100 and 200 mg/kg males and 200 mg/kg females were significantly greater than those of controls. The incidences of syncytial alteration in all male dose groups and in 200 mg/kg females were also significantly greater than controls. The incidences of eosinophilic foci, a putative preneoplastic lesion, and of hepatocellular adenoma were significantly greater in the 50 and 100 mg/kg females. Hepatocellular carcinomas occurred with low incidences in the dosed females, but none occurred in the controls. The overall incidence of hepatocellular neoplasms (benign and malignant combined) in the 50 and 100 mg/kg females (control, 8/50; 50 mg/kg, 27/49; 100 mg/kg, 31/51; 200 mg/kg, 13/50) exceeds the range in historical controls (range 2%-34%; 129/898, 14.4%) from recent NTP studies. The reason for a lack of liver response in 200 mg/kg female mice is not known, but may be due in part to the decrease in body weight. While the incidences of eosinophilic foci were marginally greater in dosed male mice, the incidences of hepatocellular neoplasms were similar among the dosed and control groups. The incidences of alveolar/bronchiolar adenomas were significantly greater in 200 mg/kg male and female mice than in the controls. Further, the incidence of alveolar/bronchiolar carcinoma in 200 mg/kg females was also significantly greater than in controls. The overall incidence of pulmonary neoplasms (benign and malignant combined) in the 200 mg/kg groups (males: 14/50, 9/50,15/50, 25/51; females: 2/51, 5/49, 7/49, 27/51) exceeds the range in historical controls (males: range 6%-28%; 166/900, 18.4%; females: range 0%-14%; 58/899, 6.5%) from recent NTP studies. The incidence of squamous cell papilloma of the forestomach in 50 mg/kg males was greater than that of the controls (2/50, 8/50, 2/50, 0/51) and also exceeds the range of this neoplasm in control male mice from recent NTP studies (range 0%-14%; 27/902, 3.0%). The incidence of squamous cell papilloma of the forestomach in 50 mg/kg female mice was also slightly increased (1/52, 5/50, 2/51, 2/51); however, the incidence did not exceed the NTP historical range (27/901, 3%; range, 0%-10%). GENETIC TOXICOLOGY: Coumarin induced gene mutations in Salmonella typhimurium strain TA100 in the presence, but not in the absence, of exogenous metabolic activation (S9); no mutations were induced in strains TA98, TA1535, or TA1537, with or without S9. In Chinese hamster ovary cells, coumarin induced sister chromatid exchanges in the absence of S9, and chromosomal aberrations in the presence of S9. Coumarin did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster treated either as adults by feeding or injection, or as larvae by feeding. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood of male and female B6C3F1 mice administered coumarin by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver. Synonyms: 5,6-benzo-alpha-pyrone, 2H-1-benzopyran-2-one, 2H-benzolblpyran-2-one, 1,2-oxo-1,2-benzopyran, 1,2-benzopyrone, cis-o-coumarinic acid lactone, coumarinic anhydride, cumarin, o-hydroxycinnamic acid lactone, kumarin, [2-propenoic acid, 3-(-2-hydroxyphenyl)-delta-lactone], Rattex, tonka bean camphor
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PMID:NTP Toxicology and Carcinogenesis Studies of Coumarin (CAS No. 91-64-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 89

Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular casts, and mineralization. Arsenic levels in urine, blood, kidney, and liver of dosed rats increased (140%-300%) with time on study and were proportional to the dietary concentrations of roxarsone. No compound-related hematologic or clinical chemical effects were observed in rats. In the first 13-week studies, final mean body weights of mice that received 800 ppm were 11%-18% lower than those of controls. Deaths occurred in males and females receiving 400 and 800 ppm. No compound-related gross or histopathologic lesions were observed. In the second 13-week studies in mice, no compound-related hematologic or clinical chemical effects were observed. At the end of the studies, arsenic concentrations in dosed mice ranged from 0.45 to 0.99 ug/g of liver and from 0.85 to 2.98 ug/g of kidney. No arsenic was detected in the liver or kidney of control mice. Because of kidney lesions, lower body weight gain, and increased mortality in rats and lower body weight gain and increased mortality in mice in the short-term studies, dietary concentrations of roxarsone selected for the 2-year studies were 0, 50, or 100 ppm for rats and 0, 100, or 200 ppm for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of controls. No significant differences in survival were observed between any groups of rats of either sex, although survival in males was lower than usual (final survival--male: control, 24/50; low dose, 18/50; high dose, 18/50; female: 27/50; 35/50; 32/50). The average feed consumption by high dose rats was 95% that of controls for males and 88% for females. The average amount of roxarsone consumed per day was approximately 2 mg/kg for low dose rats and 4 mg/kg for high dose rats. Mean body weights of high dose male mice were generally 5%-8% higher than those of the controls, whereas those of female mice were generally 6%-15% lower than those of the controls. The survival of the control group of male mice was lower than that of the low dose group after month 22; survival for females was low (final survir than that of the low dose group after month 22; survival for females was low (final survival--male: 27/50; 40/50; 33/50; female: 14/50; 18/50; 17/50). The low survival in females was due in part to utero-ovarian infection, with more than 50% of the animals in each dose group having suppurative inflammation at this site. The average daily feed consumption by dosed mice was 105%-110% that by the controls. The average amount of roxarsone consumed per day was approximately 21 or 43 mg/kg for low dose or high dose male mice and 27 or 54 mg/kg for low dose or high dose female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Although the incidence of adenomas of the exocrine pancreas in high dose male rats was not statistically greater than that in the controls (control, 1/50; low dose, 1/50; high dose, 5/50), it was greater than that seen in any historical control group of male F344/N rats. The historical rate is 1/437 (0.2%) for the study laboratory and 5/1,871 (0.3%) throughout the Program. The incidences of hyperplasia were 2/50; 0/50; 3/50. No hyperplasia oradenomas were observed in the exocrine pancreas of female rats. Clitoral gland adenomas in female rats occurred with a marginally positive trend (1/44; 3/47; 6/48; P=0.049). One carcinoma was also observed in each of the groups. The incidences of adenomas or of adenomas or carcinomas (combined) in the dosed groups were not significantly different from those in the controls. This marginal effect was not considered to be related to roxarsone administration. No chemical-related increases in neoplastic or nonneoplastic lesions occurred in male or female mice. Lymphomas in female mice occurred with a negative trend; the incidences in the dosed groups were lower than that in the controls (13/50; 2/50; 3/50; P≤0.01). Genetic Toxicology: Roxarsone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Roxarsone induced trifluorothymidine (Tft) resistance in mouse lymphoma L5178Y cells in the absence of metabolic activation; it was not tested with activation. Exposure of adult male Drosophila melanogaster to roxarsone by injection or by feeding did not cause an increase in sex--linked recessive lethal mutations. Audit: The data, documents, and pathology materials from the 2-year studies of roxarsone have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally increased incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 years. Synonyms: 4-hydroxy-3-nitrophenylarsonic acid; 4-hydroxy-3-nitrobenzenearsonic acid; 2-nitro-1-hydroxybenzene-4-arsonic acid; nitrophenolarsonic acid; 3-nitro-4-hydroxybenzenearsonic acid; 3-nitro-4-hydroxyphenylarsonic acid Trade Names: Ristat; Ren-O-sal; 3-nitro; 3-nitro-10; 3-nitro-20; 3-nitro-50; 3-nitro-80
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PMID:NTP Toxicology and Carcinogenesis Studies of Roxarsone (CAS No. 121-19-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1272 87

Presented here is the case of a paraneoplastic cerebral degeneration (PCD) in a female patient with breast cancer and the indication of anti-Yo antibodies in the cerebrospinal fluid (CSF) and serum. The patient's primary indications were dizziness and a severe gait ataxia. The indication of anti-Yo antibodies led to the conclusion of the existence of a paraneoplastic cerebral degeneration. The antibodies in question are anti-Purkinje-cell autoantibodies acting against the antigens common to tumor and Purkinje cells which occur in association with a certain percentage of breast or ovarian cancers. The diagnosis of the primary tumor, that is clinically undetectable with conventional imaging processes, is performed with the aid of positron emission tomography (PET) to detect the presence of axillary lymph node metastases. The micro-invasive mammary carcinoma was able to be localized with the aid of MR mammography and, after MR mammography marking, was removed. The patient subsequently received adjuvant treatment with epirubicine and cyclophosphamide. This treatment failed to influence the paraneoplastic neurological symptoms.
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PMID:Paraneoplastic neurological syndrome: patient with anti-Yo antibody and breast cancer: a case report. 1460 24

We have observed an increasing number of autopsies on patients with chemotherapy-related complications. One complication is toxic leukoencephalopathy, which is due to a direct toxic effect of chemotherapeutic agents on the central nervous system white matter. Autopsies of four cases of toxic leukoencephalopathy were performed following standard protocols. The brain and spinal cord were examined routinely, and histological sections were taken for evaluation. We report here three patients with hematologic malignancies and one patient with metastatic carcinoma with chemotherapy-induced leukoencephalopathy. The first was a 56-year-old male treated with multiple chemotherapeutics for multiple myeloma. He presented with confusion and focal seizures with a rapid progression to coma and decerebrate posturing. The second was a 36-year-old male who developed mental status changes, ataxia and dysarthria following treatment for lymphoma. The third was a 16-year-old male who developed a profound peripheral and central neuropathy after chemotherapy treatment for T-cell acute lymphoblastic leukemia. The fourth was a 49-year-old female patient who was treated with multiple chemotherapeutics for Stage II breast carcinoma and subsequently developed visual acuity and field defects. The neuropathologic findings in these cases, although similar, varied in severity and distribution. The white matter was affected by severe myelin pallor, edema, and a prominent macrophage infiltrate in each of the cases. The location and extent of the central nervous system pathology correlated with the type and severity of clinical symptoms. These four cases, with their varied presenting symptoms, clinical courses, and degree of pathology, emphasize the importance of considering toxic leukoencephalopathy as an etiology of acute neurologic deterioration following high-dose chemotherapy.
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PMID:Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies. 1470 18

Genotoxic treatments, such as UV light, camptothecin, and adozelesin, stall DNA replication and subsequently generate DNA strand breaks. Typically, DNA breaks are reflected by an increase in ataxia and Rad-related kinase (ATR)-regulated phosphorylation of H2AX (gammaH2AX) and require replication fork movement. This study examined the potential of the monofunctional DNA alkylating agent hedamycin, a powerful inhibitor of DNA replication, to induce DNA strand breaks, phosphorylated H2AX (gammaH2AX) foci, and chromosome aberrations. Hedamycin treatment of HCT116 carcinoma cells resulted in a rapid induction of DNA strand breaks accompanied by increasing H2AX phosphorylation and focalization. Unlike many other treatments that also stall replication, such as UV, camptothecin, and adozelesin, gammaH2AX formation was not suppressed in ATR-compromised cells but actually increased. Similarly, hedamycin induction of gammaH2AX is not dependent on ataxia telangiectasia mutated or DNA-protein kinase, and pretreatment of cells with the phosphatidylinositol 3-kinase-related kinase inhibitor caffeine did not substantially reduce induction of H2AX phosphorylation by hedamycin. Furthermore, the DNA replication inhibitor aphidicolin only modestly depressed hedamycin-induced gammaH2AX formation, indicating that hedamycin-induced DNA double-strand breaks are not dependent on fork progression. In contrast, camptothecin- and adozelesin-induced gammaH2AX was strongly suppressed by aphidicolin. Moreover, after 24 hours following a short-term hedamycin treatment, cells displayed high levels of breaks in interphase nuclear DNA and misjoined chromosomes in metaphase cells. Finally, focalization of a tightly bound form of Ku80 was observed in interphase cells, consistent with the subsequent appearance of chromosomal aberrations via abnormal nonhomologous end joining. Overall, this study has revealed a disparate type of DNA damage response to stalled replication induced by a bulky DNA adduct inducer, hedamycin, that seems not to be highly dependent on ATR or DNA replication.
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PMID:Hedamycin, a DNA alkylator, induces (gamma)H2AX and chromosome aberrations: involvement of phosphatidylinositol 3-kinase-related kinases and DNA replication fork movement. 1609 33


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