Oxidation of extracellular thiol/disulfide redox state sensitizes cells to chemical-induced toxicity. Oxidative stress increases expression of death receptor components, Fas and Fas ligand (35). To determine whether changes in thiol/disulfide redox state could affect sensitivity to chemical toxicity, normal human retinal pigment epithelial cells were cultured in media with systematic variations in Cys and CySS concentrations to give a range of redox values found in vivo in human plasma and then treated with the oxidant t-butylhydroperoxide. The results showed that cells cultured at more reduced redox states were more resistant to oxidant-induced apoptosis than were cells cultured at more oxidized redox states. While it is not yet clear how general this effect is with regard to other cell types and other chemicals, the results suggest that the change in redox state, per se, may be an important determinant of susceptibility to toxicity. Together with the above findings, these results provide strong justification for exploring whether an interaction between chemical exposure and diet can induce detectable redox changes and whether diverse metabolic consequences of variation in thiol/disulfide redox state can be detected by high resolution metabolic analysis.