formation
in vivo. However, high doses (over 150
µmol/kg bw [27 mg/kg bw] had toxic
inhibitory effects (Yamaguchi et al., 1989).
(viii) Immunological effects
In the National Toxicology Program study (2002), a localized inflammatory response
was seen in the lungs of male F344/N rats and female B6C3F
1
mice exposed by inhalation
to 4, 8, or 16 mg/m
3
vanadium pentoxide in a 16-day study. Increases in cell numbers,
protein, neutrophils and lysozymes in BALF were observed but the number of macro-
phages in lavage fluids of male rats and female mice exposed to 8 or 16 mg/m
3
was
decreased. No effects were seen on systemic immunity in rats and mice.
When weanling and adult ICR mice were given 6 mg/kg bw vanadium pentoxide by
gavage (5 days per week for 6 weeks), an increase in the number of leukocytes and plaque-
forming cells, as well as enhanced phytohaemagglutinin responsiveness, increased spleen
weight and depression of phagocytosis were observed in treated mice. In Wistar rats given
vanadium pentoxide in drinking-water (1 or 100 mg/L for 6 months), the higher dose
resulted in increased spleen weight and concanavalin-A responsiveness; a depression of
phagocytosis was found in a dose-dependent manner. These results suggest activation of T-
and B-cell immune responses (Mravcová et al., 1993).
(ix)
Biochemical effects
Chakraborty et al. (1977) gave male albino rats vanadium pentoxide orally at a dose
of 3 mg/kg bw five times a week for the first week and 4 mg/kg bw for a further 2 weeks
and found that it induced histological and enzymatic alterations including inhibition of
biosynthesis, enhanced catabolism and increased use of L-ascorbic acid in the liver and
kidney tissues of the rats.
(b)
In-vitro studies
(i)
Organ culture
Garcia et al. (1981) found that treatment with vanadium pentoxide (10
–5
–10
–2
M
[1.82–1820
µg/mL]) produced dose-dependent contractions of the rat vas deferens organ
cultures in vitro; a response that could be associated with the inhibition of Na
+
/K
+
-ATPase
activity.
Schiff and Graham (1984) used organ cultures of hamster trachea to study the in-vitro
effects of vanadium pentoxide (0.1, 1, 10 or 100
µg/mL) and oil-fired fly ash (10, 50, 100
or 250
µg/mL) on mucociliary respiratory epithelium following exposure for 1 h per day for
9 consecutive days. Vanadium pentoxide was found to decrease ciliary activity and produce
ciliostasis in tracheal ring explants. The degree of change depended on the concentration and
length of exposure; early morphological alterations consisted of vacuolization of both nuclei
and cytoplasm of tracheal epithelium cells.
Preincubation of rat kidney brush border membrane vesicles with 1 mM [182
µg/mL]
vanadium pentoxide for 8 h significantly inhibited citrate uptake in a time-dependent
manner. This effect was attributed to a direct interaction of vanadium with the sodium
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citrate cotransporter. The results suggest that vanadium pentoxide has nephrotoxic poten-
tial (Sato et al., 2002).
(ii)
Cell culture
In cultures of bovine alveolar macrophages, Fisher et al. (1986) found that vanadium
pentoxide was the most cytotoxic compound when compared with other metals or
metalloids (zinc oxide, nickel sulfide, manganese oxide, sodium arsenite, sodium selenite)
tested. Vanadium caused a reduction in phagocytosis by macrophages to 50% of control
values after incubation for 20 h at a concentration of 0.3
µg/mL, but this concentration was
also associated with a substantial (59%) loss of macrophage viability. The authors con-
cluded that their results confirmed those of previous studies (Waters et al., 1974) which
demonstrated that vanadium is a unique macrophage toxicant.
Vanadium(V) and related compounds are known to exert potent toxic effects on a
wide variety of biological systems. One of the pathways of vanadium(V) toxicity is
thought to be mediated by oxygen-derived free radicals (Zychlinski et al., 1991; Shi et al.,
1997; Ding et al., 1999).
Parfett and Pilon (1995) evaluated the effects of promoters such as vanadium com-
pounds on oxidative stress-regulated gene expression and promotion of morphological
transformation in C3H/10T1/2 cells. Promoters which elevate intracellular oxidant levels
can be distinguished by a spectrum of induced gene expression which includes the oxi-
dant-responsive murine proliferin gene family. Proliferin transcription was found to be
induced 20-fold by 5
µM [0.9 µg/mL] vanadium pentoxide. Another pentavalent vana-
dium, ammonium metavanadate (5
µM [0.6 µg/mL]), added as promoter in two-stage
morphological transformation assays, amplified yields of Type II and Type III foci in
monolayers of 20-methylcholanthrene-initiated C3H/10T1/2 cells. These results suggest
that pentavalent vanadium compounds could promote morphological transformation in
these cells by creating a cellular state of oxidative stress, which induces the expression of
proliferin. Proliferation of MCF-7 cells was found to be stimulated after 4-day treatments
with 0.5–2
µM vanadium(V); the effect reached a plateau at 1 µM vanadium, declined at
3
µM and disappeared at 5 µM (Auricchio et al., 1995; 1996).
To determine the effect of vanadium pentoxide on the release of two major immuno-
regulatory cytokines, mouse macrophage-like WEHI-3 cells were treated in vitro (Cohen
et al., 1993). Vanadium pentoxide decreased the release of IL-1 and TNF
α stimulated
with lipopolysaccharide endotoxin. Spontaneous release of the IL-1/TNF-regulating pros-
tanoid prostaglandin E
2
(PGE
2
) was significantly increased by the highest concentration
of ammonium metavanadate tested, although lipopolysaccharide endotoxin-stimulated
PGE
2
production was unaffected. These results showed that pentavalent vanadium could
alter the host’s immunocompetence. In another study with WEHI-3 cells treated with
100
µM or 100 nM vanadium pentoxide or ammonium metavanadate, the capacity of
macrophage-like cells to bind and respond to interferon
γ was altered (Cohen et al., 1996).
When mice and rat hepatocytes or human Hep G2 cells were treated in vitro with
vanadium pentoxide (1, 10 or 100
µM), gene expression (after 2-h treatment) and
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