It has been suggested that the measurement of DNA-protein cross-links (DPCs) may be of value in the assessment of an individual's exposure to specific environmental insults. For a biomarker to be reliable, its results should be consistent and specific. In the present study, the precision and specificity of the K(+)-SDS precipitation assay as a measurement for DPCs was assessed. Chinese hamster ovary (CHO) and human fibroblast cells were exposed to a number of diverse oxidative insults, whose concentrations ranged from physiological to super-physiological levels. Only super-physiological concentrations of the insults induced the formation of DPCs. Formaldehyde, chromate, vanadate, acetaldehyde, and copper were found to be the greatest inducers of DPC formation followed by manganese and iron. DPC induction was consistently higher in the CHO cells than in human fibroblast cells. While the K(+)-SDS assay may be of value as an indicator of cumulative DNA damage, its value as a biomarker for specific environmental insults may be limited.