Vanadium pentoxide

secretion of IL-8, MIP-2 chemokines and TNF

α (after 18-h treatment) were increased.

The induction of IL-8 and MIP-2 secretion was inhibited by antioxidants such as tetra-

methylthiourea and N-acetylcysteine, showing that the events responsible for this gene

expression involve cellular redox changes (Dong et al., 1998). Vanadium pentoxide

caused a several-fold increase in heparin-binding epidermal growth factor-like growth

factor (HB-EGF) mRNA expression and protein in normal human bronchial epithelial

cells and increased the release of HB-EGF mitogenic activity of these cells (Zhang et al.,

2001a). 

Wang and Bonner (2000) showed that vanadium pentoxide activated extracellular

signal-regulated kinases 1 and 2 (ERK-1/2) in rat pulmonary myofibroblasts. This acti-

vation was an oxidant-dependent event and required components of an epidermal growth

factor-receptor signalling cascade.

Ingram  et al. (2003) showed that vanadium pentoxide stimulated HB-EGF mRNA

expression and hydrogen peroxide production by human lung fibroblasts. Both vanadium

pentoxide and hydrogen peroxide activated ERK-1/2 and p38 MAP kinases. Inhibitors of

these two kinase-pathways significantly reduced both vanadium and H

2

O

2

-induced HB-

EGF expression. These data indicate that vanadium upregulates HB-EGF via ERK and

p38 MAP kinases.

Evidence suggests that some forms of vanadium (sodium metavanadate, peroxovana-

date and pervanadate) or vanadium-containing particles from environmental and occupa-

tional sources can trigger or potentiate apoptosis. The pentavalent form of vanadium has

been shown to cause apoptosis in a JB6 P

+

mouse epidermal cell line (Cl 41) and in lym-

phoid cell lines, but may be anti-apoptotic in others such as malignant glioma cells

(Hehner et al., 1999; Chin et al., 1999; Huang et al., 2000; Chen et al., 2001). 

Rivedal et al. (1990) found that vanadium pentoxide exposure for 5 days promoted the

induction of morphological transformation of hamster embryo cells pre-exposed to a low

concentration of benzo[a]pyrene for 3 days. However, when vanadium pentoxide (0.25, 0.50

or 0.75 

µg/mL) was tested in the Syrian hamster embryo (SHE) assay, the results were nega-

tive after a 24-h exposure, but significant morphological transformation was produced after

a 7-day exposure. This pattern of response (24-h SHE negative/7-day SHE positive) has

been seen with other chemicals (i.e., 12-O-tetradecanoylphorbol 13-acetate, butylbenzyl

phthalate, methapyrilene) that have tumour promotion-like characteristics (Kerckaert et al.,

1996a,b). 

(iii)

Cell-free systems

In cell-free systems, vanadium(V) caused the oxidation of thiols, including GSH and

cysteine, and induced the formation of thiyl radicals (Shi et al., 1990; Byczkowski &

Kulkarni, 1998). It has been shown that depletion of GSH not only decreases the antioxi-

dant defence in the cytosol, but also prevents regeneration of a vital lipid-soluble antioxi-

dant, 

α-tocopherol, thereby increasing the vulnerability of phospholipid-rich biomem-

branes to oxidative stress and lipid peroxidation (Byczkowski & Kulkarni, 1998).

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Vanadium can inhibit a variety of enzymes such as heart adenyl cyclase and protein

kinase, ribonucleases, phosphatases, and several adenosinetriphosphatases (ATPases), but

it can stimulate a number of others. The enzymes inhibited include phosphoenzyme ion-

transport ATPases, acid and alkaline phosphatases, Na

+

+K

+

ATPase, H

+

+K

+

ATPase, phos-

photyrosyl protein phosphatase, dynein (contractile protein ATPase associated with micro-

tubules of cilia and flagella), myosin ATPase, phosphofructokinase, adenylate kinase and

cholinesterase (Nechay, 1984; WHO, 1988).

Vanadium(V) appears to undergo a redox cycling when the inner mitochondrial mem-

brane permeability barrier to vanadate polyanions is broken. It has been proposed that

vanadium(V) stimulates the oxidation of NAD(P)H by biological membranes and

amplifies the initial generation of O

2

–

•

produced by membrane-associated NAD(P)H oxi-

dase. This stimulatory effect is due to interaction of vanadium(V) with O

2

–

•

but not with

the membrane-associated enzymes (Liochev & Fridovich, 1988).

Using ESR spin trapping, Shi and Dalal (1992) demonstrated that rat liver micro-

somes/NADH, in the absence of exogenous H

2

O

2

, generated hydroxyl (

•

OH) radicals

from the reduction of vanadium(V) via a Fenton-like mechanism. This radical generation

may play a role in vanadium(V)-induced cellular injury.

4.3

Reproductive and developmental effects

4.3.1

Humans

No data were available to the Working Group.

4.3.2

Experimental systems

(a)

In-vivo studies

Several studies describe the reprotoxic (male or female reproductive capability) and

developmental (teratological) effects of vanadium pentoxide (Lagerkvist et al., 1986;

Domingo, 1994; Leonard & Gerber, 1994; Domingo, 1996; Leonard & Gerber, 1998;

National Toxicology Program, 2002).

(i)

Toxicokinetics in pregnant animals

Li et al. (1991) treated non-pregnant and pregnant Wistar rats with 5 mg/kg vanadium

pentoxide intraperitoneally and reported the tissue distribution of this compound. Non-

pregnant rats had significant concentrations of vanadium in kidney, ovary, uterus and liver,

suggesting that female genital organs are important target organs in the distribution of

vanadium. Treatment of pregnant rats gave similar results, including the presence of vana-

dium in the placenta. The authors suggested that vanadium could pass the blood–placenta

barrier.

Zhang  et al. (1991a) analysed the passage of vanadium across the placenta into the

embryo/fetus of pregnant Wistar rats at different times after different dose regimens: 4 h

VANADIUM PENTOXIDE

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