An evaluation of the mode of action framework for mutagenic carcinogens case study II: Chromium (VI)

Abstract

In response to the 2005 revised U.S Environmental Protection Agency's (EPA) Cancer Guidelines, a strategy is being developed to include all mutagenicity and other genotoxicity data with additional information to determine whether the initiating step in carcinogenesis is through a mutagenic mode of action (MOA). This information is necessary to decide if age-dependent adjustment factors (ADAFs) should be applied to the risk assessment. Chromium (VI) [Cr (VI)], a carcinogen in animals and humans via inhalation, was reassessed by the National Toxicology Program (NTP) in 2-year drinking water studies in rodents. From these data, NTP concluded that the results with Cr (VI) showed clear evidence of carcinogenicity in male and female mice and rats. Cr (VI) is also mutagenic, in numerous in vitro assays, in animals (mice and rats) and in humans. Accordingly, Cr (VI) was processed through the MOA framework; postulated key steps in tumor formation were interaction of DNA with Cr (VI) and reduction to Cr (III), mutagenesis, cell proliferation, and tumor formation. Within the timeframe and tumorigenic dose range for early events, genetic changes in mice (single/double-stranded DNA breaks) commence within 24 hr. Mechanistic evidence was also found for oxidative damage and DNA adduct formation contributing to the tumor response. The weight of evidence supports the plausibility that Cr (VI) may act through a mutagenic MOA. Therefore, the Cancer Guidelines recommend a linear extrapolation for the oral risk assessment. Cr (VI) also induces germ cell mutagenicity and causes DNA deletions in developing embryos; thus, it is recommended that the ADAFs be applied.

Hexavalent chromium-induced erythrocyte membrane phospholipid asymmetry

“…Chromium pollution is a major health hazard in distinct mining areas (Das and Singh 2011). Chromium (VI) may be absorbed in the intestine and triggers oxidative stress, inflammation, cell proliferation, malignant transformation, growth arrest, cytotoxicity, and apoptosis (Chiu et al 2010;Holmes et al 2008;McCarroll et al 2010;Nickens et al 2010;Stout et al 2009; Thompson et al 2011;Wise et al 2008;Yao et al 2008). Mechanisms implicated in chromium (VI) toxicity include mitochondrial damage as well as DNA damage including base modification, single-strand breaks, double-strand breaks, Cr-DNA adducts, DNA-Cr-DNA adducts, protein-Cr-DNA adducts, and mutagenesis (Asatiani et al 2010;Chiu et al 2010;Hartwig 1995;Wise et al 2008).…”

Geogenic and Anthropogenic Chromium Contamination in Groundwater in an Ophiolitic Area, Northeastern Iran

“…Ingestion of hexavalent chromium in drinking water by human changes hexavalent chromium to trivalent chromium with the formation of Cr-DNA adducts and other DNA damage resulting in mutagenesis, cell proliferation and tumor formation in the GI tract California [20,21,22,23] (Figure 12). The World Health Organization (WHO) in 2003 [10]set the provisional guideline value for total chromium in drinking water at 50µg/l.…”

Scientific opinion on genotoxicity testing strategies applicable to food and feed safety assessment

“…The drug doxorubicin is a known example of this kind of complex action, but also chemicals relevant to food safety may display multiple mechanisms of genotoxic activity. For example, some metal ions can cause oxidative stress, interact with proteins involved with genome stability and form adducts on DNA (McCarroll et al, 2010). Similarly, topoisomerase inhibition, a potential cause of DNA breakage, was reported also to affect DNA repair; a reduced activity of the incision step of nucleotide excision repair was observed in human fibroblasts treated with different topoisomerase I and II inhibitors (Thielmann et al 1993).…”