Impacts of antioxidants on hydroxyl radical production from individual and mixed transition metals in a surrogate lung fluid

Inhalation of ambient particulate matter causes morbidity and mortality in humans. One hypothesized mechanism of toxicity is the particle-induced formation of reactive oxygen species (ROS) – including the highly damaging hydroxyl radical (OH) – followed by inflammation and a variety of diseases. While past studies have found correlations between ROS formation and a variety of metals, there are no quantitative measurements of OH formation from transition metals at concentrations relevant to 24-hour ambient particulate exposure. This research reports specific and quantitative measurements of OH formation from 10 individual transition metals (and several mixtures) in a cell-free surrogate lung fluid (SLF) with four antioxidants: ascorbate, citrate, glutathione, and uric acid. We find that Fe and Cu can produce OH under all antioxidant conditions as long as ascorbate is present and that mixtures of the two metals synergistically increase OH production. Manganese and vanadium can also produce OH under some conditions, but given that their ambient levels are typically very low, these metals are not likely to chemically produce significant levels of OH in the lung fluid. Cobalt, chromium, nickel, zinc, lead, and cadmium do not produce OH under any of our experimental conditions. The antioxidant composition of our SLF significantly affects OH production from Fe and Cu: ascorbate is required for OH formation, citrate increases OH production from Fe, and both citrate and glutathione suppress OH production from Cu. MINTEQ ligand speciation modeling indicates that citrate and glutathione affect OH production by changing metal speciation, altering the reactivity of the metals. In the most realistic SLF (i.e., with all four antioxidants), Fe generates approximately six times more OH than does the equivalent amount of Cu. Since levels of soluble Fe in PM are typically higher than those of Cu, our results suggest that Fe dominates the chemical generation of OH from deposited particles in the lungs.