The mutagenicity and carcinogenicity of inorganic manganese compounds: a synthesis of the evidence.

Manganese (Mn), a naturally occurring element present in many foodstuffs, is an essential trace element with many biological functions. In industry, inorganic Mn compounds have a range of different applications, although the majority of Mn is used to make alloys and steel. For the general population, the major source of exposure to Mn is dietary, although drinking water may constitute an additional source in some regions. However, in occupationally exposed humans, inhalation of Mn is likely to be an important additional route. In general, Mn and its inorganic compounds are considered to possess low mutagenic or carcinogenic potential compared with some heavy metals. In this review, an up-to-date analysis of the available published studies on the carcinogenic and genotoxic potential of inorganic Mn is provided (organic Mn compounds are not considered). The current literature indicates that Mn may be weakly mutagenic in vitro and possibly clastogenic in vivo, with unknown genotoxic effects in humans; the possible mechanisms underlying these effects are discussed. The experimental evidence on carcinogenicity (quantitative increase in incidence of thyroid tumors in mice but not rats) does not provide any clear evidence, while the available occupational and environmental epidemiological evidence is equivocal as to whether exposure to inorganic Mn is associated with a significant cancer risk. Hence, it is concluded that there is insufficient evidence to indicate that inorganic Mn exposure produces cancer in animals or humans.

A review of current toxicological concerns on vanadium pentoxide and other vanadium compounds: gaps in knowledge and directions for future research.

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.