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

Daisy P. Cross, Gurumurthy Ramachandran, Elizabeth V Wattenberg

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20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)409-418
Number of pages10
JournalAnnals of Occupational Hygiene
Issue number5
StatePublished - 2001

Bibliographical note

Funding Information:
This work was supported by a Grant-in-Aid of Research, Artistry and Scholarship from the University of Minnesota and by a University of Minnesota Academic Health Center Faculty Development Grant. The MP-48 alveolar cells were the gift of Dr David H. Ingbar, Department of Medicine, University of Minnesota. We also thank Anita Wichmann for excellent technical assistance.


  • Cobalt
  • Dosimetry
  • Exposure
  • Inhalation
  • Mixtures
  • Nickel
  • Synergism


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