A Review of Current Toxicological Concerns on Vanadium Pentoxide and Other Vanadium Compounds: Gaps in Knowledge and Directions for Future Research

Abstract

Vanadium pentoxide (V(2)O(5)) and other inorganic vanadium compounds have recently been evaluated by several occupational exposure limit (OEL) setting (occupational exposure limit, OEL) committees and expert groups in response to the publication of several new studies, including the U.S. National Toxicology Program (NTP, 2002) carcinogenicity study of inhaled V(2)O(5) in rats and mice, which concluded that clear evidence of lung tumors was seen in mice of both genders and that there was some evidence of carcinogenicity in male rats. This study reviews the expert evaluations of several OEL committees and expert groups and attempts to understand the strengths and weaknesses in their scientific arguments. This study also evaluates some key studies relating to potential genotoxicity, carcinogenicity, and respiratory effects of vanadium compounds and discusses how they might elucidate the mechanism(s) by which V(2)O(5) induces lung cancer in mice. All expert groups appear to agree that the lung tumors induced in mice in the NTP (2002) study are a site-specific response and, in general, verify that existing in vitro and in vivo studies suggest that tumors were induced by a secondary mechanism (presumably non-genotoxic), which is supported, though not conclusively, by a mechanistic data set. As some vanadium compounds produce a range of DNA and chromosome damage, there is no consensus on which of these changes is critical for the carcinogenic process for V(2)O(5) or whether the findings for the lung tumors seen in mice exposed to V(2)O(5) can be extrapolated to other inorganic vanadium compounds. As such, the various expert committees used the evidence differently, some to read across, i.e., to predict an endpoint for a substance based on the endpoint information of another with similar characteristics (e.g., physicochemical properties [solubility, bioaccessibility, bioavailability], structure, fate [toxicokinetics], and toxicology) for carcinogenicity from V(2)O(5) to other inorganic vanadium compounds. It is noteworthy that the toxicity of metals does not necessarily relate to carcinogenicity in a direct manner; thus, no assumptions should be made a priori when trying to extrapolate from V(2)O(5) to other inorganic vanadium compounds. Recent studies evaluated in this review provided some further insights into possible mechanisms but do not cover all relevant endpoints, address only a limited number of vanadium compounds, and have not established no-effect thresholds for carcinogenicity or respiratory tract irritation. Thresholds need to be established in order for arguments to be made for setting a health-based OEL for non-genotoxic or secondary genotoxic carcinogens. In conclusion, important knowledge gaps preclude confident classification and risk assessment for all vanadium compounds. Evidence suggests that further research that may address some of these critical gaps is needed.

Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks

“…Genotoxic mechanisms for tumor induction by V 2 O 5 in B 6 C 3 F 1 mice was not supported by the negative results in an Ames assay using Salmonella strains TA1535, 100, 97, 98, and 102 and the lack of evidence of micronucleus induction in peripheral blood from mice exposed to 1-16 mg/m 3 V 2 O 5 by inhalation for 3 months [14,26]. However, recent studies reported a slight increase in 8-oxodGuo DNA lesions in lungs of female B 6 C 3 F 1 mice exposed to 1 or 4 mg/m 3 V 2 O 5 for 16 days by nose-only inhalation [21], and increased micronuclei in peripheral blood in male but not female CD1 mice exposed to 1.4 mg/m 3 V 2 O 5 for 2 h per week for 4 weeks by aerosol inhalation [20].…”

Oxidative stress and metal carcinogenesis

“…Among V compounds, V pentoxide is highly toxic [101]. Similar to Ni, the pentavalent forms, such as V and vanadate, have carcinogenic potential via ROS generation, DNA damage, and activation of hypoxia signaling [200]. ROS generation and MAPK phosphorylation have been shown to play important roles in cell cycle arrest induced by vanadate [201].…”

Vanadium pentoxide: Use of relevant historical control data shows no evidence for a carcinogenic response in F344/N rats

“…Ress et al (2003) noted at the time that tumor incidence rates can be affected by diet, and as a consequence, ''use of the existing historical control database (NIH-07) may not be appropriate for all neoplasms'' (see also Haseman et al, 2003;Assem and Levy, 2009).…”