Profiling of Environmental Mixtures Containing Metals for Their Toxicity Pathways and Mechanism of Action

Superfund sites are where soil, air, and water are polluted with hazardous materials. Individuals residing and working in these areas are often exposed to metals and other hazardous materials, leading to many adverse health outcomes, including cancer. While individuals are often exposed to multiple chemicals simultaneously, the combined effect of such exposures remains largely unexplored. Here, we investigated the toxicity of metal mixtures in five categories of in vitro assays measuring cytotoxicity, oxidative stress, genotoxicity, cytokine release, and angiogenesis. After testing these mixtures in primary cells and cell lines, we discovered that the nickel/arsenic/cadmium and beryllium/arsenic/cadmium combinations exhibited higher cytotoxicity than their individual compounds, suggesting that the mixtures amplified the cytotoxic effect. To investigate the mechanism underlying their toxicity, we evaluated metal-induced oxidative stress, as oxidative stress is a common factor in most metal-related toxicities. Our results showed that cadmium-induced oxidative stress was increased in mixtures. Some mixtures that induced oxidative stress further increased DNA damage, inhibited DNA synthesis, and activated p53. In addition, some mixtures significantly increased interleukin-8 secretion and angiogenesis more than their component compounds. Our findings offer important insights into metal-related toxicity at Superfund sites.