NTP toxicology and carcinogensis studies of vanadium pentoxide (CAS No. 1314-62-1) in F344/N rats and B6C3F1 mice (inhalation).

UNLABELLED

Vanadium pentoxide, commercially the most important compound of vanadium, presents a potential occupational hazard during the cleaning of oil-fired boilers and furnaces, the handling of catalysts, and during the refining, processing, or burning of vanadium-rich mineral ores or fossil fuels. Vanadium pentoxide was nominated for study by the National Cancer Institute as a representative of the metals class study. Male and female F344/N rats and B6C3F1 mice were exposed to vanadium pentoxide (99% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Three males in the 32 mg/m(3) group died before the end of the study. Mean body weights of males and females exposed to 8 mg/m(3) or greater were less than those of the chamber controls. Clinical findings included rapid respiration and hypoactivity in rats exposed to 16 or 32 mg/m(3). Relative lung weights of 4 mg/m(3) or greater males and 2 mg/m(3) or greater females were significantly greater than those of the chamber controls. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, 4, 8, 16, or 32 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. All males exposed to 32 mg/m(3) and one 8 mg/m(3) male died or were killed moribund before the end of the study. Mean body weights of 16 mg/m(3) males and 8 mg/m(3) or greater females were significantly less than those of the chamber controls, and the 32 mg/m(3) females lost weight during the study. Absolute and relative lung weights of 4 mg/m(3) or greater males and all exposed groups of females and liver weights of 16 mg/m(3) males were significantly greater than those of the chamber controls. The mediastinal lymph nodes were enlarged in 4, 8, and 16 mg/m(3) males and females, and lymphoid hyperplasia was confirmed histologically. Lavage fluid analysis indicated an inflammatory response in the lung that was either directly mediated by vanadium pentoxide or was secondary to lung damage induced by vanadium pentoxide exposure. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. Seven males and three females exposed to 16 mg/m(3) died during the study. Mean body weights were significantly less in males exposed to 4 mg/m(3) or greater and in females exposed to 16 mg/m(3). Abnormal breathing, thinness, lethargy, abnormal posture, and ruffled fur were observed in rats exposed to 16 mg/m(3). Hematology results indicated that exposure of rats to vanadium pentoxide induced a microcytic erythrocytosis in males and females. Absolute and relative lung weights were significantly greater for 4 mg/m(3) or greater males and females than for the chamber controls as were the relative lung weights of 2 mg/m(3) males. The estrous cycle of females exposed to 8 mg/m(3) was significantly longer than that of the chamber control group, and the number of cycling females in the 16 mg/m(3) group was reduced. The incidences of several nonneoplastic lesions of the lung and nose were significantly increased in males and females exposed to 2 mg/m(3) or greater. Data from pulmonary function analyses indicated that a restrictive lung disease was present in male and female rats exposed to 4 mg/m(3) or greater, while an obstructive lung disease was present only in the 16 mg/m(3) groups. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8, or 16 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 3 months. One male exposed to 16 mg/m(3) died before the end of the study. Mean body weights of 8 and 16 mg/m(3) males and 4 mg/m(3) or greater females were significantly less than those of the chamber controls. Absolute and relative lung weights of males and females exposed to 4 mg/m(3) or greater were significantly greater than those of the chamber controls. The epididymal spermatozoal motility of males exposed to 8 or 16 mg/m(3) was significantly decreased. Some mice exposed to 2 or 4 mg/m(3) had inflammation of the lung, and all mice exposed to 8 or 16 mg/m(3) had inflammation and epithelial hyperplasia of the lung. 16-DAY SPECIAL STUDY IN RATS: Groups of 60 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, or 2 mg/m(3) and groups of 40 female rats were exposed to 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia was observed in most rats exposed to 2 or 4 mg/m(3) on days 6 and 13. Histiocytic infiltration and inflammation occurred in a time- and concentration-related manner. Cell turnover rates were increased in the terminal bronchioles on days 6 and 13 and in the alveoli in the 4 mg/m(3) group on day 6 and in all exposed groups on day 13. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 4.42 to 4.96 days. 16-DAY SPECIAL STUDY IN MICE: Groups of 60 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 2, or 4 mg/m(3) and groups of 40 female mice were exposed to 8 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 16 days. Alveolar and bronchiolar epithelial hyperplasia occurred with similar incidences and severities among the exposed groups on days 6 and 13, and time- and concentration-related increases in the incidences of interstitial inflammation and histiocytic infiltration also occurred in these groups. Cell turnover rates were increased in the terminal bronchioles on day 6 and remained greater than those of the chamber controls on day 13. In the alveoli, cell turnover rates were increased in an exposure concentration-related manner on day 13; cell turnover rates were increased only in the 8 mg/m(3) group on day 6. Assessment of lung vanadium concentrations suggested deposition and clearance exhibited linear kinetics over the exposure range studied. Lung clearance half-times ranged from 2.40 to 2.55 days. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 0.5, 1, or 2 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival and body weights of males and females were generally similar to those of the chamber controls. Mean body weights of females exposed to 2 mg/m(3) were less than those of the chamber controls throughout the study. Alveolar/bronchiolar neoplasms were present in exposed groups of male rats, and the incidences often exceeded the historical control ranges. Alveolar/bronchiolar adenomas were present in 0.5 and 1 mg/m(3) females; one 2 mg/m(3) female also had an alveolar/bronchiolar carcinoma. The incidence of alveolar/bronchiolar adenoma in the 0.5 mg/m(3) group was at the upper end of the historical control ranges. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female rats, and the severities of these lesions generally increased with increasing exposure concentration. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to particulate aerosols of vanadium pentoxide at concentrations of 0, 1, 2, or 4 mg/m(3) by inhalation, 6 hours per day, 5 days per week for 104 weeks. Survival of 4 mg/m(3) males was significantly less than that of the chamber controls. Mean body weights of 4 mg/m(3) males and all exposed groups of females were generally less than those of the chamber controls throughout the study, and those of males exposed to 2 mg/m(3) were less from week 85 to the end of the study. Many mice exposed to vanadium pentoxide were thin, and abnormal breathing was observed in some mice, particularly those exposed to 2 or 4 mg/m(3). The incidences of alveolar/bronchiolar neoplasms were significantly increased in all groups of exposed males and females. Nonneoplastic lesions related to vanadium pentoxide exposure occurred in the respiratory system (lung, larynx, and nose) of male and female mice, and the severities of these lesions generally increased with increasing exposure concentration. Bronchial lymph node hyperplasia was present in many exposed females.

MOLECULAR ONCOLOGY STUDIES

K-ras codon 12 mutation and loss of heterozygosity on chromosome 6 were detected in vanadium pentoxide-induced alveolar/bronchiolar carcinomas from mice.

GENETIC TOXICOLOGY

Vanadium pentoxide was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, TA102, or TA1535, with or without induced rat or hamster liver S9 enzymes.

CONCLUSIONS

Under the conditions of this 2-year inhalation study, there was some evidence of carcinogenic activity of vanadium pentoxide in male F344/N rats and equivocal evidence of carcinogenic activity of vanadium pentoxide in female F344/Nrats based on the occurrence of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenic activity of vanadium pentoxide in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. (ABSTRACT TRUNCATED)