Drinking water supplies in many geographic areas contain
chromium in the +3 and +6 oxidation states. Public health concerns are centered on the presence of hexavalent Cr that is classified as a known human
carcinogen via inhalation.
Cr(VI) has high environmental mobility and can originate from anthropogenic and natural sources. Acidic environments with high organic content promote the reduction of
Cr(VI) to nontoxic Cr(III). The opposite process of
Cr(VI) formation from Cr(III) also occurs, particularly in the presence of common minerals containing Mn(IV)
oxides. Limited epidemiological evidence for
Cr(VI) ingestion is suggestive of elevated risks for
stomach cancers. Exposure of animals to
Cr(VI) in
drinking water induced
tumors in the alimentary tract, with linear and supralinear responses in the mouse small intestine.
Chromate, the predominant form of
Cr(VI) at neutral pH, is taken up by all cells through
sulfate channels and is activated nonenzymatically by ubiquitously present ascorbate and small
thiols. The most abundant form of DNA damage induced by
Cr(VI) is Cr-
DNA adducts, which cause mutations and
chromosomal breaks. Emerging evidence points to two-way interactions between DNA damage and epigenetic changes that collectively determine the spectrum of genomic rearrangements and profiles of gene expression in
tumors. Extensive formation of
DNA adducts, clear positivity in genotoxicity assays with high predictive values for carcinogenicity, the shape of
tumor-dose responses in mice, and a
biological signature of mutagenic
carcinogens (multispecies, multisite, and trans-sex tumorigenic potency) strongly support the importance of the
DNA-reactive mutagenic mechanisms in carcinogenic effects of
Cr(VI). Bioavailability results and kinetic considerations suggest that 10-20% of ingested low-dose
Cr(VI) escapes human gastric inactivation. The directly mutagenic mode of action and the incompleteness of gastric detoxification argue against a threshold in low-dose extrapolation of
cancer risk for ingested
Cr(VI).