Quartz crystal microbalances (QCMs) measure mass on the nanogram (ng) scale. We built novel QCMs as toxicity biosensors incorporating living cells. Human endothelial cells or canine macrophages were equilibrated on QCM crystal surfaces until stable oscillation frequencies occurred. Vehicle or sodium azide (NaN3) (25-100 mM) was added to these QCMs while continuously collecting crystal oscillation frequency data. At these doses, NaN3 alters mitochondrial membrane permeability and causes mitochondrial swelling and intrinsic apoptosis. Our studies demonstrated no frequency change in QCMs with untreated cells or without cells but NaN3. If NaN3 was added to either cell type within QCMs, 5 to 8 min later increases in oscillation frequency (Δf) occurred (400-1600 Hz) that correlated with dose. All frequency changes reverted to baseline by 15 min. In parallel, during the first 30 min, no change in cell or nuclear areas, or in actin or microtubule distributions, was detected. Yet, mitochondrial size and membrane permeability increased significantly during, but not after, 5 to 8 min. Viability studies confirmed dose-dependent toxicity that was predicted and proportionate to the 5- to 8-min Δf. These studies confirm that cell-based QCMs can detect early events in intrinsic apoptosis and reveal unique kinetic information about events occurring within subcellular structures in response to toxins.