The underlying mode of action for lung tumors in a tiered approach to the assessment of inhaled cobalt compounds.

A mode of action (MOA) for cobalt substances based on the "International Programme on Chemical Safety Conceptual Framework for Evaluating a MOA for Chemical Carcinogenesis" is presented. The data recorded therein were generated in a tiered testing program described in the preceding papers of this special issue, as well as data from the public domain. The following parameters were included in the evaluation: solubility of cobalt substances in artificial lung fluids (bioelution), in vitro biomarkers for cytotoxicity, reactive oxygen species and hypoxia mimicry, inhalation toxicity following acute exposure and repeated dose inhalation effects. Two distinct groups of cobalt substances emerged: substances inducing all effects across the MOA form one group, associated with the adverse outcome of lung cancer in rodents upon chronic exposure. Another group of cobalt substances induces no or very limited effects in the in vitro and acute testing. Higher tier testing with a representative of this group, tricobalt tetraoxide, showed a response resembling rat lung overload following exposure to high concentrations of poorly soluble particles. Based on the fundamental differences in the lower tier toxicological profile, cobalt substances with an unknown hazard profile can be assigned to either group based on lower tier testing alone.