Abstract
Epidemiological studies in chromate production have established hexavalent chromium as a potent lung carcinogen. Inhalation of chromium(VI) most often occurs in mixtures with other metals as among stainless steel welders, which is the largest occupational group with Cr(VI) exposure. Surprisingly, carcinogenicity of Cr(VI)-containing welding fumes is moderate and not consistently higher than that of Cr-free welding. Here, we investigated interactions between chromate and three other metal ions [Fe(III), Mn(II), Ni(II)] that are typically released from stainless steel welding particles. In human lung epithelial cells with physiological levels of ascorbate and glutathione, Cr(VI) was by far the most cytotoxic metal in single exposures. Coexposure with Fe(III) suppressed cytotoxicity and genotoxicity of Cr(VI), which resulted from a severe inhibition of Cr uptake by cells and required extracellular ascorbate/glutathione. Chemically, detoxification of Cr(VI) occurred via its rapid extracellular reduction by Fe(II) that primarily originated from ascorbate-reduced Fe(III). Glutathione was a significant contributor to reduction of Cr(VI) by Fe only in the presence of ascorbate. We further found that variability in Cr(VI) metabolism among common cell culture media was caused by their different Fe content. Ni(II) and Mn(II) had no detectable effects on metabolism, cellular uptake or cytotoxicity of Cr(VI). The main biological findings were confirmed in three human lung cell lines, including stem cell-like and primary cells. We discovered extracellular detoxification of carcinogenic chromate in coexposures with Fe(III) ions and identified the underlying chemical mechanism. Our findings established an important case when exposure to mixtures causes inactivation of a potent human carcinogen.