Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The parathyroid hormone-like biological activity of concentrated urine was measured by the increase of plasma calcium concentration after intravenous injection of the sample into chickens. 2. Urine was tested in hypoparathyroid patients, normal volunteer subjects, primary hyperparathyroid patients before and after surgery and patients with secondary hyperparathyroidism. 3. In primary and secondary hyperparathyroidism the biological activity was significantly higher than in urine from normal subjects, which was in turn significantly higher than the activity in the urine of hypoparathyroid patients. This bioactivity diminished after surgical removal of a hyperparathyroid adenoma. 4. Decreased activity after trypsinization indicated the peptidic nature of the hypercalcaemic substance.
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PMID:Parathyroid hormone-like biological activity in urine. 63 65

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

Oxazepam is one of a number of benzodiazepines used therapeutically as a sedative-hypnotic and antianxiety agent. Toxicology and carcinogenesis studies were performed by administering oxazepam (greater than 99% pure) in feed to male and female Swiss-Webster and B6C3F1 mice for 14 weeks, 57 weeks (Swiss-Webster), or 2 years (B6C3F1). Neurobehavioral assessments were performed during the studies. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and peripheral blood samples were analyzed for frequency of micronucleated normochromatic erythrocytes. Supplemental studies were performed to compare the metabolism and toxicokinetics of oxazepam in the two mouse strains, to evaluate the effect on liver cell replication rates, to perform clinical pathology assessments, and to examine the mutation spectrum and frequency of activated H-ras oncogenes in liver neoplasms from the 2-year study with B6C3F1 mice. 14-WEEK STUDY IN SWISS-WEBSTER MICE: Groups of 10 male and 10 female Swiss-Webster mice received oxazepam in feed at concentrations of 0, 625, 1,250, 5,000, 10,000 ppm for 14 weeks. One 625 ppm male and one 10,000 female were killed moribund before the end of the study, and the condition of the female mouse was attributed to oxazepam exposure. Mean body weight gains of exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during the first study week, but appeared normal thereafter. In the neurobehavioral studies, reductions in grip strength were evident in both male and female mice at week 2 and persisted in males through week 11. An antianxiety effect was detected in exposed mice in measures of motor activity, startle response, and reactions to thermal stimulus. At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. 14-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female B6C3F1 mice received oxazepam in feed at concentrations of 0, Groups of 10 male and 10 female Swiss-Webster mice 625, 1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. received oxazepam in feed at concentrations of 0, There were no deaths that were clearly related to 625,1,250, 2,500, 5,000, or 10,000 ppm for 14 weeks. oxazepam exposure. Mean body weight gains of One 625 ppm male and one 10,000 ppm female were exposed groups were similar to those of the controls. Exposed mice displayed chemical-related sedation and lethargy during only the first study week. In neurobehavioral studies, reductions in grip strength were evident in males at week 2 but were no longer observed at week 12. An antianxiety effect was noted in exposed mice in measures of motor activity, startle response, and reactions to a thermal stimulus (females). At necropsy, absolute and relative liver weights were increased in an exposure-related manner and were approximately two-fold greater in 10,000 ppm mice than in controls. Centrilobular hepatocellular hypertrophy was present only in exposed mice, and the severity increased with dose. CHRONIC STUDIES: Groups of 60 male and 60 female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice received 125 ppm in feed to allow for study of a group with projected serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. Ten male and 10 female B6C3F1 mice per group were evaluated at 15 months. Average daily oxazepam consumption varied throughout the studies, and the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the 5,000 ppm groups. Serum oxazepam concentrations determined at 57 weeks in Swiss-Webster mice and at the 15-month interim evaluation of B6C3F1 mice 1 mice were approximately 1 ug/mL in the 125 ppm groups, 4 to 7 μg/mL in the 2,500 ppm groups, and 7 to 10 μg/mL in the 5,000 ppm groups. Neurobehavioral assessments during the chronic studies of each strain of mice were confounded by the poor survival and deteriorating condition of mice with hepatic neoplasia. However, within the limitations of the studies, there were no notable changes in the types of behaviors observed compared to those observed in the 14-week studies, nor was there an enhancement in the degree to which they were exhibited. 57-Week Study in Swiss-Webster Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: At 57 weeks, survival of exposed mice was significantly lower than that of controls (males: O ppm, 45/60; 2,500 ppm, 19/60; 5,000 ppm, 10/60; females: 47/60, 28/59, 17/59), causing the study to be terminated. Mean body weights of exposed males were similar to controls until week 17; afterwards, mean body weights of exposed male groups were lower than those of controls. Final mean body weights of exposed males were 9% lower than that of the controls. The mean body weight of 2,500 ppm females was greater than that of the controls throughout the study. Females receiving 5,000 ppm had a mean body weight greater than that of the controls early in the study; after week 29, the mean body weight of this group was similar to that of the controls. Feed consumption by exposed males and females was slightly lower than that by the controls, and females in all groups, including controls, consumed slightly more feed than males throughout the study. Dietary levels of 2,500 and 5,000 ppm oxazepam resulted in average daily compound consumption levels of 270 and 570 mg/kg for males and 320 and 670 mg/kg for females. Hypoactivity and sedation were observed in exposed mice during the first week of the study. There were no other clinical findings associated with oxazepam exposure. Pathology Findings: Systemic amyloidosis was the principal cause of death in mice dying before the study was terminated. The lower survival of mice receiving oxazepam was attributed to an increase in the extent and severity of amyloid deposits in many organs, including the heart and kidney. Atrial thrombosis and pulmonary lesions consistent with chronic heart failure occurred at higher incidences and with greater severity in exposed mice. The incidence of hepatocellular adenomas (males: 1/60, 35/60, 50/60; females: 0/60, 22/59, 47/59) and carcinomas (males: 0/60, 5/60,19/60; females: 1/60, 1/59, 11/59) were increased in exposed mice. The incidences of eosinophilic foci were also increased in exposed mice (males: 0/60, 22/60, 22/60; females: 0/60, 20/59, 14/59), and there was evidence of increased centrilobular hepatocyte hypertrophy (males: 12/60, 46/60, 47/60; females: 3/60, 51/59, 53/59). 2-Year Study in B6C3F1 Mice: Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of mice receiving 2,500 and 5,000 ppm was significantly lower than that of controls (males: O ppm, 45/50; 125 ppm, 44/50; 2,500 ppm, 15/50; 5,000 ppm, 0/50; females: 39/50, 41/50, 2/50, 0/50). Mean body weight gains of exposed male and female mice were similar to controls until about week 15 when weight gains for mice exposed to 2,500 or 5,000 ppm slowed in relation to controls, resulting in weight gains approximately 30% to 40% lower than those of the controls throughout the remainder of the study. Mean body weight gain of male mice exposed to 125 ppm was similar to that of the controls, while that of female mice receiving 125 ppm was 10% to 15% lower than that of the controls after about week 45. Feed consumption by exposed males and females was similar to that by controls. Dietary levels of 125, 2,500, and 5,000 ppm resulted in average daily oxazepam consumption levels of 12, 310, and 690 mg/kg body weight for males and 15, 350, and 780 mg/kg for females. In the 5,000 ppm groups, lethargy and sedation were observed in a few mice during the first week of study. Pathology Findings: The early deaths of many of the B6C3F1 mice exposed to oxazepam were attributed to a marked increase in the incidences of hepatoblastoma (males: 0/49, 2/50, 21/50, 13/50; females: 0/50, 1/50, 8/50, 8/50), hepatocellular adenoma (males: 17/49,18/50, 34/50, 32/50; females: 25/50, 35/50, 35/50, 36/50), and hepatocellular carcinoma (males: 9/49, 5/50, 45/50, 50/50; females: 9/50, 5/50, 49/50, 44/50). Moderate hypertrophy of centrilobular hepatocytes occurred in mice receiving 2,500 and 5,000 ppm (males: 0/49, 2/50, 26/50, 43/50; females: 0/50, 2/50,11/50, 29/50). An increase in the incidence of follicular cell hyperplasia of the thyroid gland occurred in all exposed groups of mice (males: 4/49, 22/50, 49/50, 47/50; females: 16/50, 34/50, 49/50, 44/50), and thyroid gland follicular cell adenoma was increased in exposed females (0/50, 4/50, 5/50, 6/50). Testicular atrophy occurred in the 2,500 and 5,000 ppm groups (1/50, 0/50, 25/50, 38/50), and the incidence of epididymal Iymphocyte infiltration was increased in all exposed groups (2/50,14/50, 33/50, 21/50). The frequency of hepatocellular neoplasms with an activated H-ras oncogene in the B6C3F1 mice and the mutation spectrum of the H-ras gene were determined. The mutation spectrum of the H-ras genes in the relatively few neoplasms from exposed mice that did have an activated H-ras did not differ from the spectrum of mutations observed in neoplasms from controls, but the proportion of neoplasms with an activated H-ras gene decreased with increasing oxazepam dose. While 11 of 19 (58%) neoplasms from control mice had an activated H-ras gene, only 1 of 40 neoplasms from mice receiving 2,500 or 5,000 ppm oxazepam exhibited a similar molecular lesion. Thirteen of 37 (35%) neoplasms from mice in the 125 ppm group had an activated H-ras oncogene, suggesting that, although the incidence of all liver neoplasms was not statistically increased compared to controls, there was an increase in a similar subset of neoplasms (lacking an activated H-ras) that occurred with increased incidence at higher doses. SUPPLEMENTAL STUDIES: Because exposure to oxazepam caused increased incidences of liver neoplasms, supplemental short-term studies were performed. Oxazepam given in feed to male B6C3F1 mice at 25, 125, 2,500, or 5,000 ppm for up to 13 weeks was found to cause a dose-related increase in nuclear labeling index in studies measuring the incorporation of bromodeoxyuridine into replicating liver cells. This increase was statistically significant at all but the 25 ppm exposure level and was limited to mice evaluated at 15 days. Cell replication rates in most groups evaluated at 30 days and after were similar to control rates. There was minimal evidence suggestive of hepatocyte necrosis either by light microscopy or in clinical chemistry measures. There was, however, evidence of cholestasis, likely due to physical obstruction of bile canaliculi by swollen hepatocytes. The metabolic fate and toxicokinetics of oxazepam were evaluated in each strain of mice and were compared to published data from human studies. Both mice and humans form glucuronides of oxazepam and form 3- and 4-hydroxy and methoxy derivatives of the phenyl group. Oxidative metabolism of the phenyl group appears to be more prevalent in mice than is reported for humans. Elimination half-lives of parent compound do not differ between Swiss-Webster and B6C3F1 mice and are similar to values reported for humans. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any of several strains of Salmonella typhimurium, nor did it induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were performed with and without S9 metabolic activation. Results from an in vivo mouse peripheral blood micronucleus test performed on the B6C3F1 mice used in the 14-week study were also negative. CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on increased incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. Administration of oxazepam to Swiss-Webster mice resulted in centrilobular hepatocellular hypertrophy and increased incidences and severity of systemic amyloidosis. Administration of oxazepam to B6C3F1 mice also resulted in centrilobular hepatocellular hypertrophy. Synonyms: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2 H - 1,4-benzodiazepin-2-one Trade Names: Tazepam, Wy-3498, Serax
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PMID:NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice (Feed Studies). 1259 20

There is widespread concern over the health effects of oxidant air pollutants. The state of California and the Health Effects Institute (HEI) (a nonprofit research institute funded jointly by the U.S. Environmental Protection Agency [USEPA] and combustion engine manufacturers) nominated ozone for evaluation in long-term animal studies. The NTP study designs were a result of a series of meetings at the NIEHS with scientists from NIEHS, USEPA, and HEI, as well as experts from academic institutions working in the area of air pollutants. Male and female F344/N rats and B6C3F1 mice were exposed to ozone by inhalation for 4 weeks, 2 years, or for 124 weeks (rats) or 130 weeks (mice). The oxygen used to generate the ozone was greater than 99.9% pure. Additional groups of male F344/N rats were administered injections of 4-(N-methyl-Nnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (~99% pure) 3 times per week for 20 weeks and exposed to ozone by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. 4-WEEK OZONE STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation 6 hours per day, 5 days per week, for a total of 20 days. All rats survived to the end of the study. The final mean body weights and mean body weight gains of 0.5 ppm males and females and of 1.0 ppm females were similar to those of the controls. The final mean body weight of 1.0 ppm males was 7% lower than that of the controls. Clinical findings included hypoactivity in 1.0 ppm males and females and ruffled fur in exposed groups of males. Male and female rats exposed to 0.5 or 1.0 ppm developed multifocal lesions of the lung, which consisted of infiltration of granulocytes and macrophages with extension of the bronchial epithelium into the alveolar ducts. Female rats exposed to ozone developed minimal squamous metaplasia of the laryngeal epithelium at the base of the epiglottis. Absolute and relative lung weights of all exposed groups of males and females were greater than those of the controls, and absolute and relative thymus weights of all exposed groups were generally lower than those of the controls. 4-WEEK OZONE STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation 6 hours per day, 5 days per week, for a total of 20 days. All mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups of mice were less than those of the controls. Hypoactivity was observed in 1.0 ppm mice. Male and female mice exposed to 0.5 or 1.0 ppm ozone developed patchy, multifocal lesions of the lung, which consisted of infiltration of granulocytes and macrophages with extension of the bronchial epithelium into the alveolar ducts. The relative lung weight of 1.0 ppm males was significantly greater than that of the controls. There were no other statistically significant differences in absolute or relative organ weights in males or females. 2-YEAR OZONE STUDY IN RATS: The 2-year study was designed to include the present USEPA standard (0.12 ppm), the maximum concentration believed compatible with long-term survival (1.0 ppm), and an intermediate concentration (0.5 ppm). Groups of 50 male and 50 female F344/N rats were exposed to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings: Survival of exposed groups of rats was similar to that of the controls at the end of the study. The mean body weights of 0.12 and 0.5 ppm males and females were similar to those of the controls throughout the study. The mean body weights of 1.0 ppm males and females were slightly lower than those of the controls throughout the study. Hypoactivity was observed in male and female rats exposed to ozone. Pathology Findings: Increased incidences of ozone-induced metaplasia occurred in the nose and lung of rats exposed to 0.5 or 1.0 ppm ozone. The lesions in the nose were characterized by an increase in the number of goblin the number of goblet cells in the respiratory epithelium with mild squamous metaplasia of the cuboidal epithelium on the lateral wall. The increase in the number of goblet cells was found primarily in level I and II epithelium occurring along the lateral wall and on the maxilloturbinates and nasoturbinates. The metaplasia in the lung was a patchy multifocal lesion consisting of extension of the bronchial epithelium into the alveoli of the centriacinar region. This may represent more an extension of the bronchial epithelium into the pulmonary parenchyma than an actual transition of one epithelial cell type into another. There were increased incidences of squamous metaplasia at the base of the epiglottis characterized by one or more layers of flattened epithelial cells where low cuboidal cells are normally found. There were no increases in the incidences of alveolar/bronchiolar adenoma or carcinoma in either males or females exposed to ozone. LIFETIME OZONE STUDY IN RATS: For this study, rats were exposed to 0.5 and 1.0 ppm ozone for an additional 6 months to determine the effect of extended exposure on neoplasm incidence. Groups of 50 male and 50 female F344/N rats were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 125 weeks. Survival, Body Weights, and Clinical Findings: Survival rates of exposed rats were similar to those of the controls. The mean body weights of 0.5 ppm males and females were similar to those of the controls throughout the study. The mean body weights of 1.0 ppm males and females were slightly lower than those of the controls for the first two years of the study. Hypoactivity was observed in exposed groups of males and females. Pathology Findings: Increased incidences of metaplasia occurred in the nose, larynx, and lung of rats exposed to 0.5 or 1.0 ppm ozone. The lung lesions were multifocal, centriacinar and were characterized by the presence of cuboidal epithelium (ciliated and nonciliated) along the alveolar ducts where type I epithelium is normally present. Inflammation (histiocytic infiltration) and interstitial fibrosis were observed in the lung of exposed males and females, and hyperplasia was observed in the nose of exposed male and female groups. There were no ozone-related increased incidences of neoplasms. 2-YEAR OZONE/NNK STUDY IN MALE RATS: An intermediate concentration of 0.5 ppm ozone was combined with exposure to two levels of a known carcinogen (0.1 and 1.0 mg NNK/kg body weight) in order to determine if ozone promotes the carcinogenic process or acts as a cocarcinogen. Groups of 48 male F344/N rats were exposed to 0 or 0.5 ppm ozone by inhalation, 6 hours per day, 5 days per week for 105 weeks. During the first 20 weeks of the study, these rats were subcutaneously injected with 0, 0.1, or 1.0 mg NNK per kg body weight in trioctanoin three times weekly. Survival and Body Weights: Two-year survival rates of male rats were similar in all groups. Final mean body weights of all males exposed to NNK alone or NNK and ozone were similar to that of the controls, with the exception of rats exposed to 1.0 mg NNK/kg body weight and 0.5 ppm ozone. Hypoactivity was observed in males exposed to NNK and ozone, in those exposed to NNK without ozone, and in those exposed to ozone only. Pathology Findings: Alveolar epithelial metaplasia and interstitial fibrosis occurred in all groups of rats exposed to ozone or to NNK and ozone, but not in those exposed to NNK without ozone. Increased incidences of hyperplasia occurred in groups of rats exposed to NNK or to ozone and NNK. Incidences of hyperplasia were similar among groups of rats exposed to NNK only. An increased incidence of alveolar/bronchiolar adenoma or carcinoma (combined) occurred in rats administered 1.0 mg/kg NNK, with or without ozone. The administration of ozone did not affect the occurrence of pulmonary neoplasms or nonneoplastic lesions in rats administered NNK. 2-YEAR OZONE STUDY IN MICE: The 2-year study was designed to include the present USEPA standard (0.12 ppm), the maximum concentration believed compatible with long-term survival (1.0 ppm), and an intermediate concentration (0.5 ppm). Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 0.12, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings: Survival rates of exposed mice were generally similar to those of the controls; the 2-year survival rate of 1.0 ppm females was greater than that of the controls. The mean body weights of 0.12 and 0.5 ppm males were similar to that of the controls throughout the study; the mean body weights of 1.0 ppm males and of all exposed groups of females were generally lower than those of the controls throughout the study. Hypoactivity was observed in male and female mice exposed to ozone. Pathology Findings: Increased incidences of metaplasia occurred in the nose and lung of mice exposed to 0.5 or 1.0 ppm ozone. The metaplasia in the nose consisted of increased thickening and extension of the squamous epithelium in the anterior portion of the nasal passage. The metaplasia in the lung consisted of extension of the bronchial epithelium into the alveoli of the centriacinar region. There were increased incidences of hyperplasia in the nose characterized by thickening of the noncuboidal (transitional) epithelium. There were increased incidences of hyperplasia in the epiglottis of female mice, a change that was characterized by a minimal increase in the thickness of the epithelium. Incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were marginally increased in 0.5 and 1.0 ppm males (0 ppm, 14/50; 0.12 ppm, 13/50; 0.5 ppm, 18/50; 1.0 ppm, 19/50) and were increased in 1.0 ppm females (6/50, 7/50, 9/49, 16/50). LIFETIME OZONE STUDY IN MICE: For this study, mice were exposed to 0.5 and 1.0 ppm ozone for 30 months to determine the effect of extended exposure on neoplasm incidence. Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 0.5, or 1.0 ppm ozone by inhalation for 6 hours per day, 5 days per week, for 130 weeks. Survival and Body Weights: Survival rates of exposed mice were similar to those of the controls. The mean body weights of 0.5 ppm males and females were similar to those of the controls throughout the study. The mean body weights of 1.0 ppm males and females were generally lower than those of the controls throughout the study. Hypoactivity was observed in male and female mice exposed to ozone. Pathology Findings: The incidences of alveolar/bronchiolar adenoma and carcinoma (combined) were marginally increased in exposed males (0 ppm, 16/49; 0.5 ppm, 22/49; 1.0 ppm, 21/50) and in exposed females (6/50, 8/49, 12/50). Increased incidences of metaplasia occurred in the nose, larynx, and lung of exposed groups of males and females, and the incidences of hyperplasia were increased in the larynx and nose of exposed mice. The morphology of the lesions was similar to that seen in the 2-year study. There were no ozone-related increases in alveolar epithelial hyperplasia. GENETIC TOXICOLOGY: Ozone was mutagenic in Salmonella typhimurium strain TA102, with and without S9 metabolic activation. CONCLUSIONS: Under the conditions of these 2-year and lifetime inhalation studies, there was no evidence of carcinogenic activity of ozone in male or female F344/N rats exposed to 0.12, 0.5, or 1.0 ppm. There was equivocal evidence of carcinogenic activity of ozone in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma or carcinoma. There was some evidence of carcinogenic activity of ozone in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma or carcinoma. There was no evidence that exposure to 0.5 ppm ozone enhanced the incidence of NNK-induced pulmonary neoplasms in male rats. Exposure of male and female rats to ozone for 2 years or 125 weeks was associated with goblet cell hyperplasia and squamous metaplasia in the nose, squamous metaplasia in the larynx, and metaplasia (extension of bronchial epithelium into the centriacinar alveolar ducts) and interstitial fibrosis in the lung. Exposure of male and female mice to ozone for 2 years or 130 weeks was associated with hyperplasia and squamous metaplasia in the nose and inflammation (histiocytic infiltration) and metaplasia (extension of bronchial epithelium into the centriacinar alveolar ducts) of the lung.
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PMID:NTP Toxicology and Carcinogenesis Studies of Ozone (CAS No. 10028-15-6) and Ozone/NNK (CAS No. 10028-15-6/ 64091-91-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1259 23