Toxicity of heavy metals in human lung A549 cells: Interaction and prediction using mixture assessment models

To investigate the joint toxicity of heavy metals (HMs) to human lung A549 cells.

Cytotoxicity was quantified by the MTT assay for both individual metals and their mixtures. Joint effects were analysed using three reference models: concentration addition (CA), independent action (IA) and the combination index (CI) equation, via the median-effect/CI methodologies.

The individual toxicity rank order was chromium [Cr(VI)] > cadmium [Cd(II)] > copper [Cu(II)] > zinc [Zn(II)] > nickel [Ni(II)] > manganese [Mn(II)] > lead [Pb(II)] > iron [Fe(II)]. The CI model approximated the actual toxicity of HMs mixtures better than the CA and IA models. Combined exposures yielded a complex interaction pattern dominated by synergism, with additive and antagonistic effects also present. Interactions varied across the effect range (fa). At three representative effect levels (Fa=0.1, Fa=0.5 and Fa=0.9), HMs mixtures exhibited single, dual and triple synergistic/ additive/ antagonistic behaviors pattern. In addition, ternary and quaternary mixtures were found to provoke stronger synergism than binary mixtures.

The CI equation is a robust tool for evaluating the diverse toxicological interactions of mixed HMs. Interactions among heavy metals are complex and predominantly synergistic, with their magnitude contingent upon the number of metal species and the effect levels.