Mixtures of nickel and cobalt chlorides induce synergistic cytotoxic effects: Implications for inhalation exposure modeling

Workers are often simultaneously exposed to two or more chemicals, yet little is known about the toxicity of most chemical mixtures. The traditional assumption, in the absence of further information, has been that the chemical components of a mixture have mutually independent effects, and the toxic response to multiple chemicals is additive. The data presented here show that mixtures of NiCl₂ and CoCl₂ induce a synergistic (that is, greater than additive) toxic response in cell culture. Immortalized alveolar epithelial type II cells were incubated for 4 h with various concentrations of either NiCl₂, CoCl₂, or NiCl₂ and CoCl₂ together, and cell viability assessed 24 h later. The LD₅₀ for NiCl₂ was 5.7 mM. CoCl₂, with an LD₅₀ of 1.1 mM, was about five times more potent than NiCl₂. Mixtures of NiCl₂ and CoCl₂ decreased cell viability synergistically. For example, a mixture of 750 μM NiCl₂ and 750 μM CoCl₂ reduced cell viability by more than three times the value predicted by the additive approach. We used concentration-response data from these studies in a mathematical model; this model describes the equivalent inhalation exposure to an aerosol composed of a mixture of chemicals with different toxicities and also accounts for synergistic responses to these chemicals. Our results along with previous studies using an animal model suggest that these synergisms should be taken into account when conducting future exposure assessments.