* National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; and
Battelle Toxicology Northwest, Richland, Washington 99352
Received January 22, 2003; accepted April 24, 2003
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ABSTRACT |
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Key Words: carcinoma; adenoma; soluble particles; lung; vanadium pentoxide; vanadium; reactive-oil-fly-ash (ROFA); inflammation; fibrosis; boilermakers bronchitis.
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INTRODUCTION |
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Although the effects of chronic inhalation exposure to V205 are not known, several studies have investigated the adverse effects following short-term exposure to V205 in primates, rodents, and humans. These studies have shown that short-term exposure to V205 results in impaired pulmonary function in monkeys, an influx of inflammatory cells in the bronchiolar lavage fluid of rats and monkeys, and fibrotic changes in the lungs of rats following whole-body inhalation or intratracheal instillation (Bonner et al., 1998, 2000
; Knecht et al., 1985
). In rats and mice exposed to V205 (whole-body) at concentrations up to 16 mg/m3 for 3 months, increases in inflammation and epithelial hyperplasia were observed at
2 mg/m3. In rats exposed to
4 mg/m3, fibrosis and a restrictive lung disease were present (NTP, 2002b
).
In humans, accidental or inadvertent exposure to V205 in the workplace has been associated with inflammatory responses in the respiratory tract, including bronchitis (often-called boilermakers bronchitis), pneumonia, rhinitis, and pharyngitis. Green discoloration of the tongue also is a common indicator of exposure to V205 (Faulkner Hudson, 1964). Workers exposed to V205 at concentrations of 0.05 and 5.3 mg/m3 developed severe respiratory tract irritation with dyspnea, a productive cough, and chest pain. Pulmonary function tests performed several days after exposure indicated the possibility of an obstructive effect on the small airways (Levy et al., 1984
). Similar symptoms have been reported in exposed boilermakers (Ross, 1983
).
To our knowledge, there are no animal or epidemiological studies investigating the carcinogenicity of V205. Because the effects of chronic inhalation exposure to V205 have not been investigated, the National Cancer Institute nominated V205 for toxicity and carcinogenicity studies to be performed by the National Toxicology Program (NTP). The purpose of this study was to investigate the toxic responses in rats and mice exposed to V205 by whole-body inhalation for 2 years. The details of this study have been reported in a technical report (NTP, 2002b). The major findings are presented here.
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MATERIALS AND METHODS |
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The stainless-steel inhalation exposure chambers (Harford Systems Division of Lab Products, Inc., Aberdeen, MD) were designed so that uniform aerosol concentrations could be maintained throughout the chambers when catch pans were in place. The total active mixing volume of each chamber was 1.7 m3.
Chamber aerosol concentrations were monitored with real-time aerosol monitors (RAMs) (Model Ram-1 MIE, Inc., Bedford, MA). Each RAM was calibrated one to two times per week by ICP/AES or ICP/mass spectrometry analysis of Pallflex® TX40H120WW glass fiber filters (Pallflex Corp., Putnum, CT). The particle size distribution in each chamber was determined prior to the start of the study and monthly thereafter using a Mercer-style seven-stage impactor (In-Tox Products, Albuquerque, NM). The mean mass median aerodynamic diameter was 1.2 and 1.3 microns for the rat and mouse chambers, respectively. The chamber environment was maintained at an airflow rate of 15 air changes per hour, a temperature of 75 ± 3°C, and a relative humidity of 55 ± 15%.
Animal use was in accordance with the United States Public Health Service policy on humane care and use of laboratory animals and the Guide for the Care and Use of Laboratory Animals. These studies were conducted in compliance with the Food and Drug Administration Good Laboratory Practice Regulations (21CFR, Part 58).
Male and female F344/N rats and B6C3F1 mice were obtained from Taconic Farms, Inc. (Germantown, NY). The animals were quarantined for approximately 2 weeks and were 6 to 7 weeks old at the beginning of the studies. Groups of 50 male and 50 female rats and mice were exposed to particulate aerosols of V205 concentrations of 0, 0.5 (rats), 1, 2, or 4 (mice) mg/m3, 6 h plus T90 (12 min) per day, 5 days per week for 104 weeks. The rats and mice were housed individually. Feed was available ad libitum, except during exposure periods; water was available ad libitum. All of the animals were observed twice daily. Clinical findings and body weights were recorded on week 1, every 4 weeks from weeks 5 through 89, and every 2 weeks from week 92 to the end of the study.
Histopathological procedures.
Complete necropsies and microscopic examinations were performed on all of the rats and mice. At necropsy, all organs and tissues were examined for gross lesions, and major tissues were fixed in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 µm, and stained with hematoxylin and eosin for microscopic examination.
Statistical methods.
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Animals found dead of other than natural causes were censored from the survival analyses; animals dying from natural causes were not censored. Statistical analyses for possible concentration-related effects on survival used Coxs (1972) method for testing two groups for equality and Tarones (1975) life-table test to identify concentration-related trends. All reported P values for the survival analyses were two-sided. The Poly-k test (Bailer and Portier, 1988
; Piegorsch and Bailer, 1997
; Portier and Bailer, 1989
) was used to assess neoplasm and nonneoplastic lesion prevalence. This test is a survival-adjusted quantal-response procedure that modifies the Cochran-Armitage linear trend test to take survival differences into account. Organ and body weight data were analyzed with the parametric multiple comparison procedures of Dunnett (1955)
and Williams (1971
, 1972
).
Historical control data.
The concurrent control group represents the most valid comparison to the treated groups and is the only control used in the statistical analyses in NTP bioassays. Until recently, the NTP historical control database consisted of animals fed an NIH-07 diet. In 1995, the NTP changed the diet fed to animals used in toxicity and carcinogenicity studies. The new diet (NTP-2000) contains less protein and more fiber and fat than the NIH-07 diet previously used and was instituted to increase longevity and decrease the incidence and/or severity of some spontaneous neoplastic and nonneoplastic lesions in rats and mice used in NTP studies (Rao, 1996, 1997
). These studies of V2O5 are among the first to use the NTP-2000 diet. Because the incidence of some neoplastic and nonneoplastic lesions may be affected by the dietary change, use of the existing historical control database (NIH-07) may not be appropriate for all neoplasms.
Currently, the database includes 11 (10 for male rats) studies by various routes in which the NTP-2000 diet was used. Because the historical database for the NIH-07 diet is more extensive, we have included these rates in the tables and in interpretation of the neoplastic response.
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RESULTS |
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Alveolar-epithelial hyperplasia and bronchiolar-epithelial hyperplasia were increased in the lungs of male rats exposed to 0.5 mg/m3 or greater and female rats exposed to 1 or 2 mg/m3 (Table 3). At 2 mg/m3, the severity of these lesions was increased. In all of the exposed mice, incidences of alveolar epithelial hyperplasia and bronchiolar epithelial hyperplasia were increased (Table 4
). This was a diffuse change, with proliferation of the epithelium in the distal terminal bronchioles and immediately associated alveolar ducts and alveoli. Normally flattened alveolar epithelium was replaced with cuboidal epithelium. The hyperplasia of the alveolar epithelium was pronounced and increased in severity with increasing exposure concentration, while the hyperplasia of the distal bronchioles was minimal to moderate in the rats and minimal to mild in the mice.
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Minimal to mild chronic active inflammation and interstitial fibrosis were significantly increased in the lungs of the male rats exposed to 1 or 2 mg/m3 and female rats exposed to 2 mg/m3. The incidence of histiocytic cellular infiltrate of the alveolus was increased in all exposed males and females (Table 3). The inflammatory lesions were primarily minimal to mild and consisted of interstitial and perivascular infiltrates of predominantly mononuclear inflammatory cells that were occasionally within the alveoli. Some alveolar septa were thickened by thin strands of eosinophilic fibrillar material (fibrosis).
In the mice, incidences of chronic inflammation and histiocytic infiltrate were significantly increased in all exposed groups, and the incidences of interstitial fibrosis were increased in the mice exposed to 2 or 4 mg/m3. The inflammatory lesions were similar to those observed in the rats. The most prominent histiocytic infiltrate occurred within the alveoli that were in close proximity to A/B neoplasms, particularly carcinomas. In some instances, the foamy macrophages filled the adjacent alveoli. Additionally, minimal numbers of histiocytes were observed in areas of alveolar and bronchiolar epithelial hyperplasia and appeared to be a primary exposure effect. Ideally, these two histiocytic changes would have been separated diagnostically; however, this was not possible because the change associated with bronchiolization was subtle and because neoplasms were prevalent in the exposed animals. Thin strands of eosinophilic fibrillar material (fibrosis) occasionally thickened the alveolar septa. This change was most notable in areas of intense histiocytic infiltrate secondary to the neoplasms.
Squamous metaplasia of the respiratory epithelium of the epiglottis was observed in the exposed rats and mice. In the rats, increased incidences of chronic inflammation of the larynx, degeneration, and hyperplasia were also observed (Tables 3 and 4). These changes were relatively minimal, commonly occur in NTP inhalation studies, and are frequently observed as a response to laryngeal injury (NTP, 2002b
).
In the nose, mild goblet cell hyperplasia of the nasal respiratory epithelium was observed in all groups of the exposed male rats and in the female rats exposed to 2 mg/m3, but not in the mice (Tables 3 and 4). In the mice, increased incidences of minimal to mild suppurative inflammation of the nose were observed at 2 or 4 mg/m3 (Table 4
). The inflammation consisted of focal aggregates of few to moderate numbers of neutrophils generally subjacent to the epithelium of the turbinates, septum, or lateral wall of the anterior nose. In the more severe cases (predominantly in females exposed to 4 mg/m3), a short segment of the overlying epithelium was ulcerated (necrosis). Similarly, in some males and females, the overlying respiratory epithelium was replaced by one or more layers of flattened epithelium (squamous metaplasia), and the incidences were marginally increased in some of the exposed groups of mice.
In the mice, there were marginal but significant increases in the incidences of atrophy of the olfactory epithelium in the females exposed to 1 or 4 mg/m3, and the incidences in the exposed males, though not significant, occurred with a positive trend (Table 4). The normally thick layers of epithelium were minimally thinned due to loss of olfactory epithelium. In some cases, there was replacement of the lost epithelium by respiratory epithelium. The incidences of hyaline degeneration of the olfactory and respiratory epithelium of the nose were increased in the exposed mice. Hyaline degeneration of the nasal epithelium occurs with a high and variable spontaneous rate in aged B6C3F1 mice and may involve the respiratory and/or olfactory epithelium. The incidence and severity frequently increase with exposure to inhaled toxicants, but this lesion is not considered an important biological effect.
There were significant increases in the incidences of hyperplasia of the bronchial lymph nodes in the exposed groups of female mice, and, while not significant, a positive trend in the incidences of this lesion also occurred in the male mice, but not the rats (Table 4). Hyperplasia was characterized by diffuse enlargement (up to 3x) due to expanded numbers of normal-appearing lymphocytes. This response was considered secondary to the inflammation and/or neoplasms of the lung.
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DISCUSSION |
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A/B adenomas and especially carcinomas with metastases from the site of origin are uncommon in rats (Hahn, 1993). Historical control data for male rats fed the NTP-2000 diet indicate that only 2 of 609 control rats developed A/B carcinomas, and there was never more than one of this type of neoplasm in a study. The neoplastic response in male rats exposed to 1 mg/m3 was just within the NTP-2000 diet (all routes) or NIH-07 diet (inhalation) historical control ranges. Because of the increased incidences of A/B adenoma, A/B carcinoma, and A/B adenoma or carcinoma (combined) in the 0.5- and 2-mg/m3 groups and the rarity of these neoplasms in rats, this response, although not statistically significant, was considered to be related to exposure to V205. It is possible that the response in the female rats was also related to V205 exposure. However, because this was primarily a low-concentration adenoma effect and the overall neoplastic response in the female rats was within the historical control ranges and did not achieve statistical significance, a clear relationship between lung neoplasms and V205 exposure was not established in the female rats.
V205 exposure caused a more pronounced neoplastic response in the mice than in the rats. The incidences of A/B adenoma, carcinoma, and adenoma and carcinoma (combined) were increased in the male and female mice and exceeded the historical control ranges at all exposure concentrations. As in the rats, the neoplasms in mice were morphologically similar to those that occur spontaneously. However, many of the exposed mice had multiple A/B neoplasms, an uncommon response in the mice, and in some cases it was difficult to distinguish between multiplicity and metastases from other lung neoplasms. Mice generally are not considered to be responsive to particulate exposure for the development of lung neoplasms. In NTP particulate inhalation studies for gallium arsenide, nickel oxide, talc, and nickel subsulfide, mice were negative for carcinogenicity in the lung, except with nickel oxide, which was equivocal in female mice, but rats were positive in these studies (NTP, 1993, 1996a
, 2000
). However, clear evidence of carcinogenicity has been observed in male and female mice exposed to insoluble and soluble aerosols of substances such as indium phosphide, molybdenum trioxide, and cobalt sulfate heptahydrate (NTP, 1997
, 1998
, 2001
). In the present study, a clear neoplastic response was observed in the lungs of male and female mice.
Genetic alterations in the K-ras oncogene and the p53 tumor suppressor gene were investigated to establish if the A/B carcinomas induced in mice were unique to V205 (Devereux et al., 2002; NTP, 2003). While there was no evidence for a role of p53 loss, genetic alterations in the K-ras oncogene indicated that a high frequency of V205-induced A/B carcinomas (73%) had K-ras mutations compared to those of control B6C3F1 mice (30%) (Devereux et al., 2002
; NTP, 2002b
). Additional evidence indicated a loss of heterozygosity (LOH) on chromosome 6 (in the region of the K-ras gene) in 17 of 19 samples with K-ras mutations and a high level of mitogen-activated protein kinase (MAPK) activity in carcinomas with k-ras mutations and LOH (Devereux et al., 2002
). These findings suggest that the mechanism of lung carcinogenesis following V205 exposure was different than that of spontaneously occuring lung neoplasms.
V205 and vanadium containing reactive oil fly ash (ROFA) induce TNF-, IL-6, IL-8, and macrophage inflammatory proteins, which are mediators of pulmonary fibrogenesis and other proliferative and inflammatory responses in the lung (Bonner et al., 1998
; Pierce et al., 1996
; Silbajoris et al., 2000
). The intracellular signaling mechanism by which V205 and ROFA induce inflammatory mediators is thought to occur through a cascade of events initiated by the phosphorylation of protein kinase tyrosines. In fact, inhibition of autophosphorylation of tyrosine kinases has been shown to reduce V205-induced pulmonary fibrosis, providing evidence for this pathway (Rice et al., 1999
). In this cascade of events, MAPK is activated and initiates transcription of NF-kB, which is required for induction of TNF-
, cytokines, and chemokines (Chen et al., 1999
; Ye et al., 1999
). Because the A/B carcinomas with k-ras mutations and LOH on chromosome 6 had high levels of MAPK activity, it is possible that this pathway is associated with V205-induced carcinogenesis in mice (Devereux et al., 2002
).
Another possible mechanism of V205-induced carcinogenesis in mice is through the formation of 8-hydroxy-2'-deoxyguanosine, a common type of oxidative base damage that has been associated with carcinogenicity. In vitro studies have shown that vanadium (IV) causes DNA strand breaks when incubated with hydrogen peroxide and forms 8-hydroxy-2'-deoxyguanosine (Sakurai, 1994; Shi et al., 1996a
,b
). In humans and other mammals, vanadium (V) is reduced to vanadium (IV), indicating a potential for DNA damage from vanadium (V) exposure (Crans et al., 1998
; Sakuri, 1994; Shi et al., 1996a
,b
).
The mechanistic evidence that V205 may be inducing genetic damage through direct mutations, induction of LOH, or through oxygen radical formation is somewhat at odds with information from in vitro bacterial mutation studies, which are generally negative (Leonard and Gerber, 1994; NTP, 2002b
). In addition, negative results were obtained in micronucleus tests in cultured Syrian hamster embryo cells (Gibson et al., 1997
) and in the peripheral blood of mice exposed to V205 by whole-body inhalation for 90 days (NTP, 2002b
). However, positive micronucleus results have been reported in Chinese hamster V79 cells and were attributed to increases in the kinetochore-positive fraction, indicating that the micronuclei contained entire chromosomes (Zhong et al., 1994
). Consistent with this, vanadium has been shown to interfere with microtubule assembly and spindle formation in human lymphocytes in vitro (Ramirez et al., 1997
). Thus, vanadium may be capable of causing genetic damage through a variety of potentially unrelated mechanisms.
Vanadium lung burden was investigated in the 2-year study for female rats and mice (NTP, 2002b). In general, vanadium lung burden increased early in the studies proportionate to exposure concentration and appeared to reach a steady state in the lowest exposure groups for both rats and mice. However, a decline in lung burden was observed in both species at the two highest exposure concentrations as the study progressed. This may have been a result of a progressive impairment in the pulmonary function resulting in lower deposition with increasing exposure time (NTP, 2002b
). While deposition patterns were similar between the rats and mice, the maximum lung burdens occurred much later in the rats (day 173) than in the mice (days 26 to 54), and the calculated elimination half-lives of vanadium were approximately six- to ninefold shorter in the mice than in the rats. Based on lung burden data, there was no evidence of particle overload in either species.
A wide range of nonneoplastic proliferative lesions in the lungs were observed in the rats and mice exposed to V205 for 2 years. The incidences of hyperplasia of the alveolar and bronchiolar epithelium were increased in exposed rats and mice and, although given two separate diagnoses, were considered to be one pathogenic process. This change was striking and appeared more prominent than has been observed in other NTP inhalation studies. Although the exact pathogenesis was not determined in the present study, morphologically, the hyperplasia of the alveolar and bronchiolar epithelium was consistent with bronchiolization, a process where bronchiolar epithelium proliferates and migrates down into alveolar ducts and adjacent alveoli. While there was clearly proliferation, it was thought primarily to represent a metaplastic change. Whether this represented a precursor lesion for development of pulmonary neoplasms is not known. However, one might assume an association in the mice because the incidences of both hyperplasia and neoplasia were very high. In contrast, the hyperplasia in the rats, although qualitatively similar to that observed in the mice, was somewhat more severe, but fewer neoplasms occurred in the rats. Also, the incidences of pulmonary neoplasms were the same in rats exposed to 0.5 or 2 mg/m3, but bronchiolization was much greater in incidence and severity in the 2-mg/m3 group. In another NTP study, high incidences of bronchiolization were observed in the male and female mice given p-nitrotoluene in dosed feeds (NTP, 2002a) with only slight increases in the incidence of lung neoplasms in the male mice. Admittedly, there could be subtle morphological differences in the hyperplastic lesions between the rats and mice that were not identified by light microscopy.
Squamous metaplasia of the alveolar epithelium occurred in some male and female rats exposed to 2.0 mg/m3 V205 in the 2-year study. Stratified squamous epithelium is not a normal component of the lung parenchyma. Its occurrence in the lung is considered to represent a response to injury. Some degree of squamous metaplasia is common in animals exposed to inhaled particulates, and this lesion has been observed in various NTP inhalation studies, including indium phosphide and cobalt sulfate heptahydrate (NTP, 1998, 2001
). Although generally consistent with the range of squamous metaplasia seen in other studies, there was a greater degree of keratinization of the lesions in the study of V205. In the squamous epithelium of the skin, there is proliferation of the basal layer with gradual keratinization and sloughing of the superficial layers. With squamous metaplasia of the alveoli, similar proliferation occurs, and the keratinized material often collects and in some cases forms cysts, as occurred in this study.
Squamous metaplasia generally occurs within areas of moderate to severe chronic inflammation, but this association was not strong in rats exposed to V205. The squamous metaplasia in this study appeared to have more layers, more keratin production, and the lesions were often focally extensive and more proliferative than one might expect with simple squamous metaplasia. Therefore, squamous cell carcinoma was considered to be a differential diagnosis in some instances. Although these lesions were quite florid, there were several features that suggested that they were not squamous cell carcinoma. The most definitive evidence of malignant neoplasia is distant metastasis, which was not seen in any of the animals. Local invasion is another trait of malignant neoplasia that was not an obvious component in the squamous lesions in this study. Additionally, areas of respiratory metaplasia were often admixed with the squamous metaplasia. This would not be expected with neoplasia, particularly squamous cell carcinoma. However, the pathogenesis or biological behavior of these lesions was not determined.
In conclusion, there was clear evidence of carcinogenicity in male and female mice exposed to V205 and some evidence of carcinogenicity in male rats based on A/B neoplasms. The relationship between A/B neoplasms and V205 exposure in female rats was considered equivocal. V205 exposure also caused a spectrum of nonneoplastic lesions, including pulmonary fibrosis, alveolar and bronchiolar epithelial hyperplasia, "bronchiolization," and minimal to mild inflammation in rats and mice. Based on lung burden data developed in female rats and mice (NTP, 2002b), it appears that the inflammatory response in rats and mice was not due to particle overload, but instead resulted from an unknown mechanism, one likely directly associated with V205. It is important to note that these responses occurred at or only slightly above the permissible human occupational exposure limit of 0.5 mg/m3 (NIOSH, 1997
).
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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Bonner, J. C., Lindroos, P. M., Rice, A. B., Moomaw, C. R., and Morgan, D. L. (1998). Induction of PDGF receptor- in rat myofibroblasts during pulmonary fibrogenesis in vivo. Am. J. Physiol. 274, L72L80.[ISI][Medline]
Bonner, J. C., Rice, A. B., Moomaw, C. R., and Morgan, D. L. (2000). Airway fibrosis in rats induced by vanadium pentoxide. Am. J. Physiol. 278, L209L216.[ISI]
Chen, F., Demers, L. M., Vallyathan, V., Ding, M., Lu, Y., Castranova, V., and Shi, X. (1999). Vanadate induction of NF-6B involves I6B kinase and SAPK/ERK kinase 1 in macrophages. J. Biol. Chem. 274, 20, 307320.
Code of Federal Regulations (CFR) 21, Part 58.
Cox, D. R. (1972). Regression models and life-tables. J. R.. Stat. Assoc. B34, 187220.
Crans, D. C., Amin, S. S., and Keramidas, A. D. (1998). Chemistry of relevance to vanadium in the environment. In Vanadium in the Environment. Part One: Chemistry and Biochemistry (J. O. Nriagu, Ed.), pp. 7396. John Wiley and Sons, New York.
Devereux, T. R., Holliday, W., Anna, C., Ress, N., Roycroft, J., and Sills, R. C. (2002). Map kinase activation correlates with k-ras mutation and loss of heterozygosity on chromosome 6 in alveolar bronchiolar carcinomas from B6C3F1 mice exposed to vanadium pentoxide for 2 years. Carcinogenesis 23, 17371743.
Dunnett, C. W. (1955). A multiple comparison procedure for comparing several treatments with a control.J. Am. Stat. Assoc. 50, 10961121.[ISI]
Faulkner Hudson, T. G. (1964). Vanadium. Toxicology and Biological Significance (E. Browning, Ed.). Elsevier Monographs on Toxic Agents. Elsevier Publishing Company, Amsterdam.
Gibson, D. P. Brauninger, R., Shaffi, H. S., Kerckaert, G. A., Leboeuf, R. A., Isfort, R. J., and Aardema, M. J. (1997). Induction of micronuclei in Syrian hamster embryo cells: Comparison to results in the SHE cell transformation assay for the National Toxicology Program test chemicals. Mutat. Res. 392, 6170.[ISI][Medline]
Hahn, F. F. (1993). Chronic inhalation bioassays for respiratory tract carcinogenesis. In Toxicology of the Lung, Target Organ Toxicology Series (D. E. Gardner, J. D. Crapo, and R. O. McClellan, Eds.), 2nd ed., p. 435. Raven Press, New York.
Kaplan, E. L., and Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457481.[ISI]
Knecht, E. A., Moorman, W. J., Clark, J. C., Lynch, D. W., and Lewis, T. R. (1985). Pulmonary effects of acute vanadium pentoxide inhalation in monkeys. Am. Rev. Respir. Dis. 132, 11811185.[ISI][Medline]
Leonard, A., and Gerber, G. B. (1994). Mutagenicity, carcinogenicity and teratogenicity of vanadium compounds. Mutat Res. 317, 8188.[ISI][Medline]
Levy, B. S., Hoffman, L., and Gottsegen, S. (1984). Boilermakers bronchitis. J. Occup. Med. 26, 567570.[ISI][Medline]
Mamane, Y., and Pirrone, N. (1998). Vanadium in the atmosphere. In Vanadium in the Environment. Part One: Chemistry and Biochemistry (J. O. Nriagu, Ed.), pp. 3772. John Wiley and Sons, New York.
Mohr, U., Rittinghausen, Takenaka, S., Ernst, H., Dungworth, D. L., and Pylev, L. N. (1990). Tumours of the lower respiratory tract and pleura in the rat. In Pathology of Tumours in Laboratory Animals (V. S. Turusov and U. Mohr, Eds.), pp. 275285. Oxford University Press, Oxford.
National Institute for Occupational Safety and Health (NIOSH) (1997). NIOSH Pocket Guide to Chemical Hazards, p. 328. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, Washington, DC.
National Toxicology Program (NTP) (1993). Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807966) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 421. NIH Publication of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1996a). Toxicology and Carcinogenesis Studies of Nickel Oxide (CAS No. 1313-99-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 451. NIH Publication No. 96-3367. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1996b). Toxicology and Carcinogenesis Studies of Nickel Subsulfide (CAS No. 12035-72-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 453. NIH Publication No. 96-3369. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1997). Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313-27-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 462. NIH Publication No. 97-3378. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (1998). Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate (CAS No. 10026-24-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 471. NIH Publication No. 98-3961. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (2000). Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 492. NIH Publication No. 00-3951. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (2001). Toxicology and Carcinogenesis Studies of Indium Phosphide (CAS No. 22398-80-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 499. NIH Publication No. 01-4433. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (2002a). Toxicology and Carcinogenesis Studies of p-Nitrotoluene (CAS No. 99-99-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 498. NIH Publication No. 02-4432. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
National Toxicology Program (NTP) (2002b). Toxicology and Carcinogenesis Studies of Vanadium Pentoxide (CAS No. 1314-62-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 507. NIH Publication No. 02-4441. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
Piegorsch, W. W., and Bailer, A. J. (1997). Statistics for Environmental Biology and Toxicology, Section 6.3.2. Chapman and Hall, London.
Pierce, L. M., Alessandrini, F., Godleski, J. J., and Paulauskis, J. D. (1996). Vanadium-induced chemokine mRNA expression and pulmonary inflammation. Toxicol. Appl. Pharmacol. 138, 111.[CrossRef][ISI][Medline]
Portier, C. J., and Bailer, A. J. (1989). Testing for increased carcinogenicity using a survival-adjusted quantal response test. Fundam. Appl. Toxicol. 12, 731737.[CrossRef][ISI][Medline]
Ramirez, P., Eastmond, D. A., Laclette, J. P., and Ostrosky-Wegman, P. (1997). Disruption of microtubule assembly and spindle formation as a mechanism for induction of aneuploid cells by sodium arsenite and vanadium pentoxide. Mutat. Res. 386, 291298.[CrossRef][ISI][Medline]
Rao, G. N. (1996). New diet (NTP-2000) for rats in the National Toxicology Program toxicity and carcinogenicity studies. Fundam. Appl. Toxicol. 32, 102108.[CrossRef][ISI][Medline]
Rao, G. N. (1997). New nonpurified diet (NTP-2000) for rodents in the National Toxicology Program toxicology and carcinogenesis studies. J. Nutr. 127, 842s846s.[Medline]
Rice, A. B., Moomaw, C. R., Morgan, D. L., and Bonner, J. C. (1999). Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am. J. Pathol. 155, 213221.
Ross, D. S. (1983). Case study: Exposure to vanadium pentoxide. Occup. Health (Lond.) 35, 6771.
Sakurai, H. (1994). Vanadium distribution in rats and DNA cleavage by vanadyl complex: Implication for vanadium toxicity and biological effects. Environ. Health Perspect. 102, 3536.
Shi, X., Jiang, H., Mao, Y., Ye, J., and Saffiotti, U. (1996a). Vanadium(IV)-mediated free radical generation and related 2'-deoxyguanosine hydroxylation and DNA damage. Toxicology 106, 2738.[CrossRef][ISI][Medline]
Shi, X., Wang, P., Jiang, H., Mao, Y., Ahined, N., and Dalal, N. (1996b). Vanadium(IV) causes 2'deoxyguanosine hydroxylation and deoxyribonucleic acid damage via free radical reactions. Ann. Clin. Lab. Sci. 26, 3949.[Abstract]
Silbajoris, R., Ghio, A. J., Samet, J. M., Jaskot, R., Dreher, K. L., and Brighton, L. E. (2000). In vivo and in vitro correlation of pulmonary map kinase activation following metallic exposure.Inhal. Toxicol. 12, 453468.[CrossRef][ISI][Medline]
Tarone, R. E. (1975). Tests for trend in life table analysis. Biometrika 62, 679682.[ISI]
Williams, D. A. (1971). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics 27, 103117.[ISI][Medline]
Williams, D. A. (1972). The comparison of several dose levels with a zero dose control. Biometrics 28, 519531.[ISI][Medline]
World Health Organization (WHO) (1988). Vanadium. Environmental Health Criteria 81. WHO, Geneva.
World Health Organization (WHO) (2001). VANADIUM PENTOXIDE and Other Inorganic Vanadium Compounds. Concise International Chemical Assesment Documents Document 29.
Ye, J., Ding, M., Zhang, X., Rojanasakul, Y., Nedospasov, S., Vallyathan, V., Castranova, V., and Shi, X. (1999). Induction of TNF- in macrophages by vanadate is dependent on activation of transcription factor NF-6B and free radical reactions. Mol. Cell. Biochem. 198, 193200.[CrossRef][ISI][Medline]
Zhong, B.-Z., Gu, Z.-W., Wallace, W. E., Whong, W.-Z., and Ong, T. (1994). Genotoxicity of vanadium pentoxide in Chinese hamster V79 cells. Mutat. Res. 321, 3542.[ISI][Medline]