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PubMed1996

NTP Toxicology and Carcinogenesis Studies of Nickel Sulfate Hexahydrate (CAS No. 10101-97-0) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Nickel sulfate hexahydrate is used in nickel plating, as a mordant in dyeing and printing textiles, as a blackening agent for zinc and brass, and in the manufacture of organic nickel salts. Nickel sulfate hexahydrate was nominated by the National Cancer Institute to the NTP as part of a class study of nickel compounds for which there was little information on the toxic and carcinogenic effects of inhalation exposure. Male and female F344/N rats and B6C3F1 mice were exposed to nickel sulfate hexahydrate (greater than 98% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in L5178Y mouse lymphoma cells. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3) (equivalent to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg nickel/m(3)). Rats were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of four or five male and female F344/N rats were exposed to 0, 3.5, 15, or 30 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, two 60 mg/m(3) males, one 30 mg/m(3) female, and all 60 mg/m(3)females died before the end of the study. Final mean body weights of all exposed groups of males and females were significantly lower than those of the controls, as were mean body weight gains of male rats. Clinical findings included increased rates of respiration and reduced activity levels in rats in all exposure groups, except those exposed to 3.5 mg/m(3). Absolute lung weights of 60 mg/m(3) males and of all exposed groups of females were significantly greater than those of the controls, as were the relative lung weights of all exposed groups of males and females. Inflammation (including degeneration and necrosis of the bronchiolar epithelium) occurred in the lungs of all exposed groups of males and females. Atrophy of the olfactory epithelium occurred in the nasal passages of all exposed groups of males (except 60 mg/m(3)) and in 15, 30, and 60 mg/m(3) females. Lymphoid hyperplasia in the bronchial or mediastinal lymph nodes was observed in 30 mg/m(3) males and in 60 mg/m(3) males and females. The concentration of nickel in the lungs of all exposed groups of males and females was greater than in control animals. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to 0, 3.5, 7, 15, 30, or 60 mg nickel sulfate hexahydrate/m(3). Mice were exposed on weekdays only, for a total of 12 exposure days during a 16-day period. Additional groups of five male and five female B6C3F1 mice were exposed to 0 or 3.5 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. All core study mice exposed to 7 mg/m(3) or greater died before the end of the study; all control and 3.5 mg/m(3)mice survived to the end of the study. Final mean body weights and weight gains of 7, 15, 30, and 60 mg/m(3)males and females were significantly less than those of the controls, and clinical findings in these groups included emaciation, lethargy, and rapid respiration rates. Absolute and relative lung weights of male and female mice exposed to 7 mg/m(3) or greater were significantly greater than those of the controls. Only tissues from mice exposed to 0, 3.5, or 7 mg/m(3) were examined histopathologically. Inflammation occurred in the lungs of 3.5 and 7 mg/m(3) males and females; necrosis of the alveolar and bronchiolar epithelium was a component of the inflammation in 7 mg/m(3)males and females. In addition, atrophy of the olfactory epithelium of the nasal passages was observed in 3.5 mg/m(3) males and females. Nickel concentrations in the lungs of mice exposed to 3.5 mg/m(3) were greater than those in the controls. 13-WEEK STUDY IN RATS: Groups of ten male and ten female F344/N rats were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate (equivalent to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 mg nickel/m(3)), 5 days per week for 13 weeks. Additional groups of six male and six female F344/N rats were exposed to 0, 0.12, 0.5, or 2 mg nic mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, one 2 mg/m(3)male rat died before the end of the study; all other males and all females survived until the end of the study. Final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no significant clinical findings noted during the study. Exposure-related increases in neutrophil and lymphocyte numbers occurred and were most pronounced in female rats. With the exception of 0.12 mg/m(3)rats, absolute and relative lung weights of all exposed groups were generally significantly greater than those of the controls. Exposure-related increases in the incidence and severity of inflammatory lesions (alveolar macrophages, chronic inflammation, and interstitial infiltration) occurred in the lungs of all exposed groups of males and females. Lymphoid hyperplasia of the bronchial and/or mediastinal lymph nodes occurred in males exposed to 0.5 mg/m(3)or greater. Atrophy of the olfactory epithelium occurred in males and females exposed to 0.5, 1, and 2 mg/m(3)and in 0.25 mg/m(3)females. The concentration of nickel in the lungs of 0.5 and 2 mg/m(3) rats was greater than that in the lungs of control animals at 4, 9, and 13 weeks for males and at 13 weeks for females. 13-WEEK STUDY IN MICE: Groups of ten male and ten female B6C3F1 mice were exposed to 0, 0.12, 0.25, 0.5, 1, or 2 mg nickel sulfate hexahydrate, 5 days per week for 13 weeks. Additional groups of up to five or six male and female B6C3F1 mice were exposed to 0, 0.12, 0.5, or 2 mg nickel sulfate hexahydrate/m(3)for tissue burden studies. In the core study, four control males, three control females, and one 0.12 mg/m(3)male died before the end of the study; the deaths were not considered to be chemical related, and all other mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the controls. There were no chemical-related clinical findings. Hematology changes similar to those reported in female rats occurred in female mice, but the mice were minimally affected. The absolute and relative lung weights of 1 mg/m(3)males and 2 mg/m(3)males and females were significantly greater than those of the controls. Increased numbers of alveolar macrophages occurred in all males and females exposed to 0.5 mg/m(3)or greater. Chronic active inflammation and fibrosis occurred in 1 and 2 mg/m(3)males and females. Lymphoid hyperplasia of the bronchial lymph node and atrophy of the olfactory epithelium in the nasal passages were observed in 2 mg/m(3)males and females. Nickel concentration in the lung of 2 mg/m(3)females was significantly greater than in control animals. 2-YEAR STUDY IN RATS: Groups of 63 to 65 male and 63 to 64 female rats were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.12, 0.25, or 0.5 mg/m(3) (equivalent to 0, 0.03, 0.06, or 0.11 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female rats from each group were evaluated at 7 months for histopathology; an additional seven males and seven females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; and five males and five females from each group were evaluated at 15 months for alterations in hematology, nickel tissue burden in the lung and kidney, and histopathology. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. Mean body weights of 0.5 mg/m(3)female rats were slightly lower (6% to 9%) than those of the controls throughout the second year of the study; final mean body weights of all exposed groups of males and 0.12 and 0.25 mg/m(3)females were similar to those of the controls. There were no clinical findings or hematology differences that were considered to be related to nickel sulfate hexahydrate administration. Pathology Findings No exposure-related neoplasms occurred in male or female rats exposed by inhalation to nickel sulfate hexahydrate for 2 years. Increased incidences of inflammatory lung lesions were generally observed in all exposed groups of male and female rats at the end of the study. The incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis were markedly increased in male and female rats exposed to 0.25 or 0.5 mg/m(3). Increased incidences of lymphoid hyperplasia in the bronchial lymph nodes occurred in 0.5 mg/m(3)male and female rats at the end of the 2-year study. The incidences of atrophy of the olfactory epithelium in 0.5 mg/m(3)males and females were significantly greater than those in controls at the end of the study. Tissue Burden Analyses Lung nickel burdens in exposed male and female rats were greater than those in the controls at the 7- and 15-month interim evaluations, and lung nickel burdens values increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 80 male and 80 female mice were exposed to nickel sulfate hexahydrate by inhalation at concentrations of 0, 0.25, 0.5, or 1 mg/m(3) (equivalent to 0, 0.06, 0.11, or 0.22 mg nickel/m(3)). Animals were exposed for 6 hours plus T90 (8 minutes) 5 days per week for 104 weeks. Five male and five female mice from each group were evaluated at 7 months for histopathology; five males and five females from each group were evaluated at 7 months for nickel tissue burden in the lung and kidney; five males and five females from each group were evaluated at 15 months for alterations in hematology and histopathology; and five males and five females from each group were evaluated at 15 months for nickel tissue burden in the lung and kidney. Survival, Body Weights, Clinical Findings, and Hematology The survival rates of all exposed groups of males and females were similar to those of the controls. The mean body weights of 1 mg/m(3)males and of all exposed groups of females were lower than those of the controls during the second year of the study. There were no clinical findings or hematology differences considered to be related to chemical exposure. Pathology Findings Inflammatory lesions of the lung generally occurred in all exposed groups of male and female mice at the end of the 2-year study. These lesions included macrophage hyperplasia, chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), alveolar proteinosis, and infiltrating cells in the interstitium. Incidences of macrophage hyperplasia and/or lymphoid hyperplasia occurred in the bronchial lymph nodes of most of the 1 mg/m(3)males and females and in some 0.5 mg/m(3)females at the end of the 2-year study. Atrophy of the olfactory epithelium was observed in 0.5 and 1 mg/m(3)males and in all exposed groups of females at the end of the 2-year study. Tissue Burden Analyses At the 7- and 15-month interim evaluations, lung nickel burden parameters measured in control and exposed groups were below the limit of detection. Absolute lung weights of 0.5 and 1 mg/m(3)lung burden study females were significantly greater than those of the controls at 15 months. GENETIC TOXICOLOGY: Nickel sulfate hexahydrate (500 to 800 g/mL) was tested for induction of trifluorothymidine resistance in L5178Y mouse lymphoma cells. A positive response was observed in the absence of S9. The test was not performed with S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female F344/N rats exposed to 0.12, 0.25, or 0.5 mg/m(3) (0.03, 0.06, or 0.11 mg nickel/m(3)). There was no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female B6C3F1 mice exposed to 0.25, 0.5, or 1 mg/ m3 (0.06, 0.11, or 0.22 mg nickel/m(3)). Exposure of rats to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, macrophage hyperplasia, alveolar proteinosis, and fibrosis of the lung; lymphoid hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Exposure of mice to nickel sulfate hexahydrate by inhalation for 2 years resulted in increased incidences of chronic active inflammation, bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia, interstitial infiltration, and alveolar proteinosis of the lung; lymphoid and macrophage hyperplasia of the bronchial lymph node; and atrophy of the olfactory epithelium. Synonyms: Blue salt; hexahydrate, nickel (2+) salt; nickel monosulfate hexahydrate; nickel (2+) sulfate hexahydrate; nickel (II) sulfate hexahydrate; nickel sulphate hexahydrate; nickelous sulfate hexahydrate; nickelous sulphate hexahydrate; single nickel salt, sulfuric acid

Journal Article↗
PubMed1996

NTP Toxicology and Carcinogenesis Studies of Nickel Subsulfide (CAS No. 12035-72-2) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Nickel subsulfide is used in the manufacture of lithium batteries and is a major component in the refining of certain nickel ores. Nickel subsulfide was nominated as part of a class study of nickel compounds, for which there was little information on the toxic and carcinogenic effects of inhalation exposure. Male and female F334/N rats and B6C3F1 mice were exposed to nickel subsulfide (at least 97% pure; the mean value for the mass median aerodynamic diameter at each exposure concentration ranged from 2.0 to 2.2 mm by inhalation 6 hours per day, 5 days per week, for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and mouse peripheral blood samples were analyzed for frequency of micronucleated normochromatic erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to atmospheres containing 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel subsulfide/m(3) (equivalent to 0, 0.44, 0.88, 1.83, 3.65, and 7.33 mg nickel/m(3)) 6 hours per day, 5 days per week for a total of 12 exposure days during a 16-day period. Additionalmgroups of three male and three female rats were exposed to 0, 0.6, 2.5, or 10 mg/m(3) for tissue burden studies. One male exposed to 10 mg nickel subsulfide/m(3) in the core study died on day 14; all other rats survived until the end of the study. Final mean body weights and mean body weight gains of males exposed to 5 or 10 mg nickel subsulfide/m(3) and females exposed to 2.5, 5, or 10 mg/m(3) were significantly lower than those of the controls. Clinical findings of toxicity on day 5 of the study included labored respiration in 10 mg/m(3) males and 5 and 10 mg/m(3) females and dehydration in 5 and 10 mg/m(3) females. Absolute and relative lung weights of 2.5, 5, and 10 mg/m(3) males and all exposed groups of females were significantlymgreater than those of the controls, as was the absolute lung weight of 1.2 mg/m(3) males. Inflammation of the lung and atrophy of the nasal olfactory epithelium occurred in all exposed mgroups. The concentrations of nickel in the lungs of exposedmgroups of rats increased with exposure concentration (males, 7 to 67 mg nickel/g lung; females, 9 to 77 mg/g lung). 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were exposed to atmospheres containing 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel subsulfide/m(3) for 6 hours per day, 5 days per week for a total of 12 exposure days during a 16-day period. Additional groups of three male and three female mice were exposed to 0, 0.6, 2.5, or 10 mg/m(3) for tissue burden studies. All male and female mice exposed to 10 mg nickel subsulfide/m(3) in the core study died before the end of the study; the death of one female was accidental. One control male, one control female, and one 1.2 mg/m(3) male also died before the end of the study. Final mean body weights and mean body weight gains of 5 mg/m(3) males were significantly lower than those of the controls. Clinical findings at day 5 included labored respiration in 10 mg/m(3) males and females. The absolute lung weight of 5 mg/m(3) males, the absolute and relative lung weights of 10 mg/m(3) males and 5 mg/m(3) females, and the relative lung weight of 10 mg/m(3) females were significantly greater than those of the controls. Inflammation of the lung occurred in 2.5, 5, and 10 mg/m(3) male and female mice, fibrosis of the lung occurred in 5 mg/m(3) males and females, and lymphoid hyperplasia of the bronchial lymph nodes and atrophy of the nasal olfactory epithelium occurred in 1.2, 2.5, 5, and 10 mg/m(3) males and females. Nickel concentrations in the lung of exposed male and female mice were greater than those of the controls (males, 10 to 20 mg nickel/g lung; females, 8 to 20 mg/g lung) 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to atmospheres containing 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulfide/m(3) (equivalent to 0, 0.11, 0.22, 0.44, 0.88, and 1.83 mg nickel/m(3)) 6 hours per day, 5 days per week for 13 weeks. Additional groups of 18 male and 18 female female rats were exposed to 0, 0.15, 0.6, or 2.5 mg/m(3) for tissue burden studies. All core study rats survived until the end of the study. Final mean body weights and mean body weight gains of 2.5 mg/m(3) males were significantly lower than those of the controls; final mean body weights of all other exposure groups were similar to those of the controls. Chemical-related clinical findings included labored respiration in 2.5 mg/m(3) males and females during weeks 2 through 7. In general, neutrophil and erythrocyte counts, hematocrit values, and hemoglobin concentrations were minimally increased in exposed rats. Absolute and relative lung weights of all exposed groups were significantly greater than those of the controls. Increases in the number of alveolar macrophages, interstitial infiltrates, or incidences of chronic inflammation of the lung occurred in all groups exposed to nickel subsulfide concentrations of 0.3 mg/m(3) or greater; the severity of these lesions generally increased with increasing exposure concentration. Increases in the number of alveolar macrophages were observed in 0.15 mg/m(3) males and females. Lymphoid hyperplasia of the bronchial and mediastinal lymph nodes was observed in rats exposed to 0.3 mg/m(3) or greater. Most 0.6, 1.2, and 2.5 mg/m(3) males and females had atrophy of the nasal olfactory epithelium, and the severity generally increased with increasing exposure concentration. Nickel concentrations in the lung increased with exposure concentration and were greater than those in the controls in rats exposed for 13 weeks (males, 5 to 18 mg nickel/g lung; females, 5 to 17 mg/g lung). 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to atmospheres containing 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickel subsulfide/m(3) for 6 hours per day, 5 days per week for 13 weeks. Additional groups of six male and six female mice were exposed to 0, 0.15, 0.6, or 2.5 mg/m(3) for tissue burden studies. Final mean body weights of all exposure groups were similar to those of the controls. No chemical-related clinical findings were observed. Lymphocyte counts in 1.2 and 2.5 mg/m(3) males were minimally greater than that of the controls. Hemoglobin concentrations and erythrocyte counts in 0.3, 0.6, 1.2, and 2.5 mg/m(3) females were minimally greater than those of the controls. Absolute and relative lung weights of 1.2 and 2.5 mg/m(3) males and females were significantly greater than those of the controls. An increase in alveolar macrophages was present in mice from the 0.3 mg/m(3) and higher exposure groups. Chronic inflammation and fibrosis were observed in the lung of 1.2 and 2.5 mg/m(3) males and females. Interstitial infiltrates of lymphocytes were observed in mice exposed to 0.6, 1.2, or 2.5 mg/m(3). Lymphoid hyperplasia of the bronchial lymph nodes was observed in groups exposed to 1.2 or 2.5 mg/m(3). Atrophy of the nasal olfactory epithelium occurred in 0.6, 1.2, and 2.5 mg/m(3) males and females, and incidences and severity generally increased with increasing exposure concentration. At 13 weeks, nickel concentrations in the lungs of exposed mice were greater than those of the controls (males, 3 to 17 g nickel/g lung; females, 6 to 23 mg/g lung), and these concentrations increased with increasing exposure concentration. 2-YEAR STUDY IN RATS: Survival, Body Weights, Clinical Findings, and Hematology: Groups of 63 male and 63 female F344/N rats were exposed to 0, 0.15, or 1 mg nickel subsulfide/m(3) (equivalent to 0, 0.11, or 0.73 mg nickel/m(3)) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed males and female rats was similar to that of the controls. Mean body weights of males and females exposed to 0.15 mg/m(3) were similar to those of the controls. Mean body weights of rats exposed to 1 mg/m(3) were lower than those of the controls throughout the second year of the study. Chemical-related clinical findings included rapid and shallow breathing following exposure periods. Hematocrit values and hemoglobin concentrations in 1 mg/m(3) males and females and the erythrocyte count in 1 mg/m(3) males were mildly greater than those in the controls. Pathology Findings: In general, the absolute and relative lung weights of exposed males and females were significantly greater than those of the controls at 7 and 15 months. There were exposure-related increases in the incidences of alveolar/bronchiolar adenoma in males, alveolar/bronchiolar carcinoma in males and females, and alveolar/bronchiolar adenoma or carcinoma (combined) in males and females at 2 years. Nonneoplastic lung lesions generally observed in exposed males and females included fibrosis; chronic active inflammation; focal alveolar epithelial hyperplasia, macrophage hyperplasia, and proteinosis; bronchial lymphoid hyperplasia; and interstitial inflammation. At 2 years, there were significant exposure-related increases in the incidences of benign pheochromocytoma, malignant pheochromocytoma, and benign or malignant pheochromocytoma (combined) in males and of benign pheochromocytoma in females. The incidence of adrenal medulla hyperplasia in 1 mg/m(3) females was significantly greater than that of the controls At 2 years, the incidences of chronic active inflammation of the nose in 1 mg/m(3) females and of olfactory epithelial atrophy in 1 mg/m(3) males and females were significantly greater than those of the controls. The incidences of lymphoid hyperplasia of the bronchial lymph node in exposed males at 7 and 15 months and in exposed males and females at 2 years were significantly greater than those of the controls. Incidences of macrophage hyperplasia in the bronchial lymph node of exposed males at 15 months and exposed males and females at 2 years were greater than those of the controls. Tissue Burden Analyses: Nickel concentrations in the lungs of exposed rats were greater than those of the controls at 7 months (males, 6 to 9 mg nickel/g lung; females, 6 to 9 mg/g lung) and 15 months (males, 4 to 3 mg nickel/g lung; females, 4 to 7 mg/g lung). 2-YEAR STUDY IN MICE: Survival, Body Weights, Clinical Findings, and Hematology: Groups of 80 male and 80 female B6C3F1 mice were exposed to 0, 0.6, or 1.2 mg nickel subsulfide/m(3) (equivalent to 0, 0.44, or 0.88 mg nickel/m(3)) by inhalation for 6 hours per day, 5 days per week for 105 weeks. Survival of exposed male and female mice was similar to that of the controls. Mean body weights of 0.6 and 1.2 mg/m(3) males and females were less than those of the controls throughout the second year of the study. Chemical-related clinical findings in male and female mice included labored respiration following exposure periods. The hematocrit value and the segmented neutrophil, monocyte, lymphocyte, and total leukocyte counts in 1.2 mg/m(3) females were greater than those in the controls. Pathology Findings: Absolute and relative lung weights of exposed males and females were generally significantly greater than those of the controls at 7 and 15 months. The incidence of alveolar/bronchiolar carcinoma in 0.6 mg/m(3) females and the incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in 0.6 mg/m(3) males and 0.6 and 1.2 mg/m(3) females were significantly less than those of the controls. In general, the incidences of chronic active inflammation; bronchialization (alveolar epithelial hyperplasia), macrophage hyperplasia and proteinosis; interstitial infiltration; and fibrosis in exposed groups of males and females were greater than those of the controls at 7 and 15 months and at 2 years. The incidences of atrophy of the nasal olfactory epithelium and inflammation of the nose in exposed mice were also generally greater than those of the controls. At 2 years, the incidences of degeneration of olfactory epithelium in exposed females were significantly less than that of the controls. The incidences of lymphoid hyperplasia of the bronchial lymph node in 1.2 mg/m(3) males at 15 months, in 0.6 and 1.2 mg/m(3) females at 15 months, and in 0.6 and 1.2 mg/m(3) males and females at 2 years were significantly greater than those of the controls. The incidences of macrophage hyperplasia in 1.2 mg/m(3) males at 7 and 15 months, in 0.6 and 1.2 mg/m(3) females at 15 months, and in 0.6 and 1.2 mg/m(3) males and females at 2 years were significantly greater than those of the controls. Tissue Burden Analyses: Nickel concentrations in the lungs of exposed mice were greater than those of the controls at 7 months (males, 10 to 11 mg nickel/g lung; females, 10 to 14 mg/g lung) and 15 months (males, 12 to 20 mg nickel/g lung; females, 15 to 26 mg/g lung). GENETIC TOXICOLOGY: Nickel subsulfide was considered to be equivocal in the Salmonella gene mutation assay overall. Sporadic weakly positive and equivocal responses were obtained in strain TA100 with and without S9 metabolic activation enzymes; all other strain/activation combinations gave negative results. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from male or female mice exposed to nickel subsulfide by inhalation for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of nickel subsulfide in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma, carcinoma, and adenoma or carcinoma (combined) and on increased incidences of benign, malignant, and benign or malignant (combined) pheochromocytoma of the adrenal medulla. There was clear evidence of carcinogenic activity of nickel subsulfide in female F344/N rats based on increased incidences of alveolar/bronchiolar carcinoma and alveolar/bronchiolar adenoma or carcinoma (combined) and an increased incidence of benign pheochromocytoma of the adrenal medulla. There was no evidence of carcinogenic activity of nickel subsulfide in male or female B6C3F1 mice exposed to 0.6 or 1.2 mg/m(3). Exposure of male and female rats to nickel subsulfide by inhalation for 2 years resulted in inflammation, hyperplasia, and fibrosis in the lung; inflammation and atrophy of the olfactory epithelium in the nose; and hyperplasia in the adrenal medulla (females). Exposure of male and female mice to nickel subsulfide by inhalation for 2 years resulted in inflammation, bronchialization, hyperplasia, and fibrosis in the lung and inflammation and atrophy of the olfactory epithelium in the nose. Synonyms: Heazlewoodite, nickel subsulphide, nickel sulfide (3:2), a-nickel sulfide (3:2) crystalline, nickel sulphide, nickel tritadisulphide, trinickel disulfide

Journal Article↗
PubMedDate not supplied

[Inhalation therapy with sulphur water in ORL: clinical-experimental study].

OBJECTIVE: Several clinics and experimental researches have highlighted the utility of the inhalant mineral therapy in numerous diseases to load of the tall and low respiratory streets. Aim of the our clinical-experimental study has been that of appraise "to brief term" the curative effects and the adverse reactions of a thermal inhalant treatment with sulphur water in the care of diseases ORL apparatus (laryngitis, pharyngitis, rhinitis, rhinosynusitis), appraise the course of some End points to distance. PATIENT AND METHODS: The study has been channel on a champion of 83 subjects of which 45 of male sex and 38 of female sex with age serious equal average to 53 years +/- 2.6. The subjects of the examined champion that affections from diseases inflammatory chronic of ORL relevance (laryngitis, pharyngitis, rhinitis) were subjected to a cycle of sulphur mineral inhalant therapy disbursed with businesslike individual of inhalations to bud of vapor to the T of 38 degrees C to 20 cm from the face with duration of 10 min, follows from aerosol for likewise minutes. To the beginning and at the end of the sulphur mineral inhalant cycle has been valued the subjective symptomatology susceptible of amelioration, some End Points to distance and the adverse reactions. RESULTS: The data seem to highlight the end cycle curative sulphur mineral inhalant an significant (P < 0.05) amelioration of best part of the symptoms examined like cough, nasal itch, expectoration [etc]. The analysis of the End Points to advised Distance show an significant (P < 0.05) progressional diminution of such indicators to succession of the annual continuity of the inhalant sulphur mineral treatment. CONCLUSIONS: The results of such research seem to demonstrate that the inhalant sulphur mineral therapy can induced notable benefit in different inflammatory chronic diseases of ORL relevance in peculiar in the first ten of life with a positive relapse on some End Points to distance and an excellent local and systemic tolerable.

Female↗
PubMedDate not supplied

[Efficacy of the inhalation of warm mineral water from Moravci well MT-6 in patients with chronic obstructive lung disease].

In 20 patients with chronic obstructive pulmonary disease (COPD) the effects of inhalation of Bisolvon (BS) were compared with the inhalations of thermomineral water of the well MT.6 of thermal spring Moravci (TMW). It was found that mean maximal expiratory flow during inhalations of TMW was statistically significantly higher from that during inhalation of BS (P less than 0.05). By visually-analogous scale the patients during inhalations of TMW were found to have statistically smaller dyspnea (P less than 0.001) and after inhalation of TMW they could expectorate much better (P less than 0.01) in comparison with the period of inhalations with BS. The authors consider the inhalations of TMW to be a good method of therapy of patients with COPD.

Adult↗
PubMed1988

[Substance abuse with inhalants].

In this article, Charles Vaille maintains that for the past two decades there has been a renewed outbreak of substance abuse with inhalants among youth throughout the world. He asserts that this phenomenon can no longer be considered as limited to a few isolated incidents. The volatile substances are common place, inexpensive, and unlike other drugs, legal; they are subject to neither international nor national controls. The specificity of addicts to inhalants renders prevention very difficult. Vaille discusses this point after describing the following two types of inhalant addiction: 1. Inhalation of gas fumes: two examples of youths inhaling fumes are cited followed by a description of ways in which inhaling or "sniffing" is performed. Vaille then presents the short-term effects of the "high", both psychological and physical. He then proceeds to disclose the harmful long-term effects concluding that addiction due to inhaling fumes seems to be developed throughout Europe. 2. Forced hyperventilation: a detailed description of how the "game" of forced hyperventilation is played is followed by a discussion of its effects on health. In discussing regulatory measures, Vaille maintains that a country's first effort at preventing substance abuse is to limit and modify the existence of such substances. After describing the various means attempted, he concludes that these effects will always result in an elusive prevention, due to the extraordinary number of inhalant substances as well as the enticing aspect of the "forbidden fruit". Regulatory measures offer an answer to those seeking a clear conscience rather than attempting to get at the root of the problem.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Exercise-induced asthma after inhalation of aerosols with different osmolarities.

Five adult asthmatics completed five standardized exercise tests while inhaling aerosols with different osmolarities. The nebulized solutions were 2% NaCl (osmolarity = 616 mosm), 4% NaCl (osmolarity = 1232 mosm), 6.1% dextrose (osmolarity = 308 mosm = isoosmolar), 24.4% dextrose (osmolarity = 1232 mosm) and distilled water (osmolarity = 0). All the patients had EIA. During the study all conditions, except the osmolarity of the inhaled aerosols were kept constant. There was no statistical difference in the response to the exercise on the five days, the fall in PEF being 22.8% after exercise while inhaling 2% NaCl, 17.8% after inhaling 4% NaCl, 16.2 after inhaling 6.1% dextrose, 24.8% after inhaling 24.4% dextrose and 21.6% after exercise while inhaling nebulized distilled water, respectively. It is concluded that the osmolarity of the inhaled aerosol is of little or no importance in exercise-induced asthma.

Adult↗
PubMed1994

[A study of relationships among solvent inhalation, personality and expectancy; especially on affinity to hallucination, sensation seeking and neurotic tendency].

94 delinquents in two homes for resocialization were surveyed to elucidate the relationship among the status of volatile solvent inhalation, expectancy and personality. The subjects were classified into solvent-inhalation group and non-solvent-inhalation group, and the former was divided into solvent dependence group and abuse group according to DSM-III-R. Each group was given personality tests; general health questionnaire (GHQ), sensation seeking scale (SSS), the vividness of visual imagery (VVIQ), test of visual imagery control (TVIC) and Yatabe-Guilford test (YG). In addition we investigated expectancy and mental symptoms caused by inhalation in it. The results are summarized as follows; 1. Inhalation group scored higher on SSS than non-inhalation group. 2. Compared with abuse group, dependence group presented with 1) higher GHQ score meaning neurotic tendency; 2) higher TVIC score meaning imagery-control-ability; 3) a higher incidence of day-dream and hallucination, especially egosyntonic type; 4) higher expectancy of "enhancement of positive affection", "reduction of negative affection" and "hallucination seeking"; 5) lower expectancy of "association with friends". 3. Higher scored inhalers on TVIC showed visual hallucinations, especially egosyntonic type more frequently than lower ones. 4. Significant correlations were recognized between GHQ score and expectancy of "reduction of negative affection", and between lack of objectiveness score of YG subscale and "hallucination seeking" expectancy. These results suggested that 1) beginning of inhalation is associated with sensation seeking trait, 2) progression to solvent dependence is correlated with three expectancies, i.e., seeking egosyntonic hallucinations paralleling high imagery-control-ability and subjectivity, reducing negative affection paralleling neurotic tendency, and enhancing positive affection. According to the findings, indulgence to drug induced positive imagery led delinquents into splitting of personality. In their treatment we need to help them to integrate high imagery ability and sensation seeking for recovery.

Adolescent↗
PubMed1994

Inhaled nitric oxide in congenital hypoplasia of the lungs due to diaphragmatic hernia or oligohydramnios.

OBJECTIVE: We determined whether inhaled nitric oxide (NO) could improve systemic oxygenation in human neonates with hypoplastic lungs. METHODS: A multicenter nonrandomized investigation was performed to study the efficacy of short-term NO inhalation. Inhaled NO was administered at 80 ppm to nine neonates without evidence of structural cardiac disease by echocardiography. Lung hypoplasia was due to congenital diaphragmatic hernia (CDH) in eight patients and to oligohydramnios in one patient. A total of 15 trials of NO inhalation were performed in these nine patients. Eight trials in seven patients were performed before extracorporeal membrane oxygenation ((ECMO); one patient had two trials) and seven trials were performed in five patients after decannulation from ECMO (two patients had two trials each). RESULTS: NO inhalation before ECMO did not change postductal PaO2 (42 +/- 3 mmHg vs 42 +/- 4 mmHg), oxygen saturation (SpO2; 89% vs 88%) or oxygenation index (31 +/- 4 cm H2O/torr vs 31 +/- 4 cm H2O/torr) for the group. All patients required ECMO support, which lasted from 5 to 17 days (mean 9). After decannulation from ECMO, NO inhalation increased postductal PaO2 from a median of 56 mm Hg (range 41 to 94) to a median of 113 mm Hg (range 77 to 326), P < .05. It decreased the oxygenation index from a median of 23 cm H2O/torr (range 11 to 7) to a median of 11 cm H2O/torr (range 4 to 21), P < .05. It increased SpO2 from 91% to 96% (P < .05) and pH from 7.48 +/- .03 to 7.50 +/- .03. CONCLUSION: In our patients with hypoplastic lungs, inhaled NO was effective only after ECMO. This could be due to maturational changes such as activating the endogenous surfactant system. Inhaled NO may be effective in neonates with hypoplastic lungs who have recurrent episodes of pulmonary hypertension after ECMO, even if they were previously unresponsive.

Extracorporeal Membrane Oxygenation↗
PubMed1994

Changing asthma mortality and sales of inhaled bronchodilators and anti-asthmatic drugs.

BACKGROUND: Increasing rates of death from asthma in the United States have stabilized somewhat since 1988. Case-control studies have suggested possible adverse effects of inhaled beta-adrenergic agonists that may have contributed to mortality. OBJECTIVE: To examine possible relationships between changing asthma mortality and sales of inhaled antiasthmatic drugs. METHODS: The National Center for Health Statistics supplied numbers and rates of death from asthma (ICD 493) by year. The Bureau of the Census supplied population data. IMS America provided estimates of total hospital and drugstore sales of inhaled beta-adrenergic agonists, cromolyn sodium, and inhaled corticosteroids by year and annual sales of AeroChambers and InspirEase kits. I calculated sales of the antiasthmatic drugs as puffs per person in the general population or doses per person for cromolyn sodium, defining a dose as a 20-mg capsule or vial or 2 mg by metered dose inhaler. RESULTS: Rates of death from asthma in the United States increased from 0.8 per 100,000 general population in 1977 and 1978 to 2.0 in 1989, then decreased to 1.9 in 1990 before increasing again to 2.0 in 1991. Rates of death for blacks 5 through 34 years of age increased from 0.9 in 1980 to 1.3 in 1990 and decreased to 1.2 in 1991. Estimated total hospital and drugstore sales of beta-adrenergic metered dose inhalers increased from 10.3 puffs per person in the general population in 1976 to 31.0 in 1991; those for inhaled corticosteroids, from 0.44 puffs per person in 1976 to 5.44 in 1991. Sales of cromolyn increased from 0.047 doses per person in 1978 to 0.91 in 1991. Sales of AeroChambers and InspirEase kits have also increased. CONCLUSIONS: Since 1988 there has been some moderation in increases in rates of death from asthma while progressive increases in sales of inhaled antiasthmatic drugs have continued. These data are consistent with the likelihood that previous increases in rates of death from asthma were partly due to undertreatment.

Aerosols↗
PubMed1993

Use of pressurised aerosol inhalers among patients attending the Chest Clinic and Primary Care Department of University Hospital, Kuala Lumpur.

Eighty consecutive patients who came to collect their prescriptions for pressurised aerosol inhalers at the Pharmacy of the University Hospital, Kuala Lumpur, were interviewed regarding their use of the pressurised inhaler. Their inhaler technique was also assessed. A significant proportion inhaled the steroid aerosol before the bronchodilator and 23.5% used the steroid inhaler for relief of acute dyspnoea. Only 28.8% of the 80 patients performed correctly all 6 steps necessary for the proper use of inhalers. The most common mistake was the failure to inhale slowly and deeply. Patients who had used the device for more than 5 years performed better, while correct inhaler technique was not dependent on the patient's sex, age or level of education.

Adolescent↗
PubMed1998

Comparison of efficacy and ease of handling of salmeterol and terbutaline powder inhalers.

A multicentre, randomised, open, parallel-group study was performed to compare the efficacy, tolerability and ease of handling of salmeterol xinafoate 50 micrograms twice daily via the Diskus inhaler with terbutaline sulphate 500 micrograms four times daily via the Turbuhaler inhaler. Two hundred and sixty-three patients (aged 18-79 years, baseline FEV1 50-90% predicted, mean PEFR 85% of response to salbutamol) were randomised to treatment with salmeterol (n = 136) or terbutaline (n = 127). A statistically significant difference in favour of salmeterol was seen between treatment groups for the primary efficacy variable, mean morning PEFR (difference in adjusted means 25.4 l/min, p < 0.001). Within the groups randomised to each device, ease of handling assessments favoured the Diskus inhaler over the Turbuhaler inhaler. More patients liked the Diskus inhaler than the Turbuhaler inhaler (98% vs 72%, p < 0.001). The Diskus inhaler received better scores than the Turbuhaler inhaler for all features assessed in the device questionnaire.

Adolescent↗
PubMed2006

Evaluation of pulmonary vascular response to inhaled iloprost in heart transplant candidates with pulmonary venous hypertension.

OBJECTIVE: Chronic left-heart failure is often associated with the development of pulmonary venous hypertension. In heart transplant candidates this is of great significance because the healthy donor heart has to compensate the increased right-ventricular afterload. Right-ventricular dysfunction is still responsible for 19% of all early deaths after orthotopic heart transplantation. Careful preoperative assessment of pulmonary vascular resistance by right-heart catheterization is essential. Reversibility testing is generally carried out to clarify therapeutic options for the post-transplant period. The objective of this case series is to report our institutional experience with inhaled iloprost compared to the common used oxygen/nitroglycerin method for reversibility testing. METHODS: Right-heart catheterization was performed in 23 patients with severely impaired left-ventricular function (EF < or = 25%, pVO2 < or = 14 ml/kg/min, NYHA III or IV) with combined pulmonary venous hypertension (TPG > 12 mm Hg and or PVR > 250 dyn x s x cm(-5)). An intraindividual comparison was performed between of the hemodynamic effect with oxygen/nitroglycerin s.l. and inhaled iloprost. RESULTS: The transpulmonary gradient fell significantly from an initial 16 mm Hg to 13 mm Hg on oxygen/nitroglycerin s.l. compared to 10 mm Hg on inhaled iloprost. Pulmonary vascular resistance fell significantly from an initial 344 dyn x s x cm(-5) to 270 dyn x s x cm(-5) on oxygen/nitroglycerin s.l. compared to 209 dyn x s x cm(-5) on inhaled iloprost. On inhaled iloprost a moderate systemic effect was noticed. CONCLUSION: In heart transplant candidates with pulmonary venous hypertension reversibility testing with inhalation of iloprost is a save method and significantly more effective than the combination of inhaled oxygen plus nitroglycerin s.l.

Administration, Inhalation↗
PubMed2004

How to achieve good compliance with inhaled asthma therapy.

Inability to use inhaler devices correctly is a major source of non-compliance in patients with asthma. The problem of coordinating dose release with inspiration seen with pressurised metered dose inhalers (pMDIs) is overcome by dry powder inhalers (DPIs), since they use inspiratory flow energy to carry the drug dose to the respiratory tract. The first DPIs were not popular because they were single dose devices and inconvenient to use. The introduction of multiple dose DPIs improved the image of the dry powder systems in the eyes of both the clinician and the patient. The continued development of DPIs has led to inhaler devices which include dose counters, are easy to use, are refillable and provide feedback to the patient on a correct inhalation. Criteria that may improve patient compliance with an inhaler include: correct use of the device by most patients; ease and convenience of device use; dose release even at low inspiratory flow rates; feedback of drug release which could instill confidence that the dose has been inhaled; cartridge refills and overall confidence in the device. The Novolizer has all the desirable features listed above and is expected to improve compliance if prescribed for the large number of patients who cannot use the conventional pMDI or less efficient DPSs.

Administration, Inhalation↗
PubMed2003

Perioperative anxiety and postoperative behavioural disturbances in children undergoing intravenous or inhalation induction of anaesthesia.

BACKGROUND: There are few published data comparing the psychological effects of intravenous (i.v.) and inhalation methods of anaesthesia induction in children. In the present study, we compared perioperative anxiety and postoperative behavioural changes in children undergoing standardized i.v. induction with thiopental and inhalation induction with sevoflurane for routine ear, nose and throat surgery. METHODS: Children were randomly assigned to receive inhalation induction with sevoflurane or i.v. induction with thiopental. Anxiety was assessed on arrival, at induction and 30 min after transfer to the recovery room using a four-point scale. The incidence of postoperative behavioural disturbances was determined using a postoperative questionnaire. RESULTS: Significantly more children were anxious during induction in the i.v. group than in the inhalation group [23 of 50 (46%) versus 5 of 50 (10%); P = 0.0001]. Mean induction time was shorter (5.6 versus 7.0 min; P = 0.0001) and recovery time longer (30.5 versus 10.4 min; P = 0.0001) in the i.v. group compared with the inhalation group. Problematic behavioural changes were reported in the first 2 weeks after surgery in nine of 32 children (28%) in the i.v. group and 16 of 34 (48%) children in the inhalation group (P = 0.13). CONCLUSIONS: Although children were more anxious during i.v. induction than inhalation induction, there was no difference in the incidence of behavioural disturbances in the first 2 weeks postoperatively.

Adolescent↗
PubMed2002

Estimation of the dose of fluticasone propionate inhaled by infants after bronchiolitis: Effect on urinary cortisol excretion.

BACKGROUND: Information on the dose of steroid infants inhale from spacer devices and its potential effect on adrenal suppression is limited. OBJECTIVE: We sought to determine the total dose of fluticasone propionate (FP) inhaled from a spacer device (Babyhaler) with face mask attachment by infants recovering from acute bronchiolitis and the effect of inhaled FP on the infants' overnight urinary cortisol/creatinine ratios (UCCRs). METHODS: Infants studied were recovering from acute bronchiolitis. In study 1, 22 infants inhaled 150 microg of FP through the Babyhaler. The likely inhaled dose was estimated by trapping it on a filter held within the face mask. In study 2, 40 infants had UCCRs measured before and during 3 months of treatment with either FP (150 microg twice daily, n = 20) or placebo (n = 20). RESULTS: In study 1 the mean +/- SD dose of captured FP was 12.8 +/- 6.9 microg (ie, 2.1 +/- 1.2 microg/kg). In study 2 the pretreatment UCCR medians (interquartile ranges) were as follows: FP, 22.8 (23.0) nmol/mmol; placebo, 24.0 (28.3) nmol/mmol. Within-group UCCR changes (median and interquartile range DeltaUCCR) were significantly different in the FP group (-8.9 and -20.6 nmol/mmol at 6 weeks and -12.6 and -25.9 nmol/mmol at 12 weeks, respectively; P =.0008) but not in the placebo group ( -5.8 and -10.7 nmol/mmol at 6 weeks and +0.3 and -17.9 nmol/mmol at 12 weeks, respectively; P =.45). Intergroup changes were insignificant in the follow-up period (6 weeks, P =.52; 12 weeks, P =.19). CONCLUSION: After bronchiolitis, infants are likely to inhale approximately 8 % of the nominal steroid dose from the Babyhaler. UCCRs can be used to monitor the bioavailability of inhaled steroids in young infants.

Acute Disease↗
PubMed2005

Particle inhalability at low wind speeds.

Accurate quantification of the dose delivered by aerosol exposures is essential for estimating the risk of potential adverse health effects. The fraction of airborne particles that can enter the nose or mouth during inhalation is referred to as the inspirable particulate mass fraction. This inhalable fraction is equivalent to delivered dose for particles greater than approximately 25 microm (aerodynamic particle diameter, d(ae)), which deposit completely and almost exclusively in the extrathoracic airways. Particle inhalability at high wind speeds (1-9 m/s) has been well characterized. However, there is a paucity of data describing the inhalability of particles at low wind speeds (< or =0.3 m/s), which are typical of indoor environments. High-wind-speed criteria poorly describe inhalability at low wind speeds. Based on the aspiration efficiencies of blunt and sharp-edged inlets, a function was developed for oral inhalability, P(I(O)), of particles at low wind speeds. This function predicts a slow decline in P(I(O)) from 0.95 at d(ae)= 8 microm, to 0.5 at d(ae) = 74 microm, and 0.1 at d(ae)= 175 microm. Data available from the literature for inhalability at relatively low wind speeds during oral breathing are well described by this logistic function (r(2)= 0.69).

Aerosols↗
PubMed2004

Pharmacoeconomics of inhaled anesthetic agents: considerations for the pharmacist.

PURPOSE: Types of economic analyses used for inhaled anesthetic agents, factors to consider in calculating the cost of inhaled anesthetics, limitations of pharmacoeconomic studies of these agents, and strategies for controlling inhaled anesthetic costs are discussed. SUMMARY: Inhaled anesthetic agents comprise a substantial component of drug budgets. Calculation of the cost of administering an inhaled anesthetic should take into consideration the cost per mL, potency, waste, concentration and duration of gas delivery, fresh gas flow rate, molecular weight, and density. The use of newer inhaled anesthetic agents with low solubility in blood and tissue provides a more rapid recovery from anesthesia than older, more soluble agents, and also provides the same level of control of depth of anesthesia at a lower fresh gas flow rate and possibly a lower cost than older agents at a higher fresh gas flow rate. A more rapid recovery may facilitate fast-track recovery and yield cost savings if it allows the completion of additional surgical cases or allows a reduction in personnel overtime expenses. Interpretation of pharmacoeconomic studies of inhaled anesthetics requires an appreciation of the limitations in methodology and ability to extrapolate results from one setting to another. Pharmacists' efforts to reduce anesthetic waste and collaborate with anesthesiologists to improve the use of these agents can help contain costs, but improving scheduling and efficiency in the operating room has a greater potential to reduce operating room costs. CONCLUSION: Much can be done to control costs of anesthetic agents without compromising availability of these agents and patient care.

Administration, Inhalation↗
PubMed2003

Respiratory deposition and inhalability of monodisperse aerosols in Long-Evans rats.

Because of limitations on conducting exposure experiments using human subjects to evaluate adverse health effects, the deposition and fate of airborne particles in animals are often studied. The results of such studies are extrapolated to humans to estimate equivalent dose and subsequent response. In this article, particle inhalability and respiratory deposition of micron-size particles are determined for female Long-Evans rats. Monodisperse aerosols were generated from a solution of radiolabeled iron chloride ((59)FeCl(3)). Long-Evans rats were exposed to the radiolabeled particles in a Cannon nose-only exposure tower to determine head, lung lobar, and total lung deposition fractions. Particle deposition fractions in a hypothetical situation, when all particles are inhalable, were found from an experimentally validated deposition model. Particle inhalability in a Cannon nose-only exposure scenario was obtained by comparing the measured deposition fractions with the predicted values for the case of 100% inhalability. Particle deposition fraction and inhalability were compared with data available in the literature. For large particles, the measured deposition fraction was lower than the literature values. Consequently, our inhalability estimates were found to be lower than previously published values. The findings here will directly affect health risk assessments in humans from exposure to airborne particles. The deposition results will improve the database on particle deposition in the lung airways of rats, and inhalability information will improve the accuracy of rat-to-human data extrapolation.

Administration, Inhalation↗