The relationship between intracellular lysosomal rupture and cell death caused by silica was studied in P388D, macrophages. After 3 h of exposure to 150 Jig silica in medium containing 1 .8 mM Ca", 60% of the cells were unable to exclude trypan blue . In the absence of extracellular Ca", however, all of the cells remained viable . Phagocytosis of silica particles occurred to the same extent in the presence or absence of Ca" . The percentage of P388D, cells killed by silica depended on the dose and the concentration of Ca" in the medium . Intracellular lysosomal rupture after exposure to silica was measured by acridine orange fluorescence or histochemical assay of horseradish peroxidase . With either assay, 60% of the cells exposed to 150 Ftg silica for 3 h in the presence or absence of Ca" showed intracellular lysosomal rupture, whereas cell death occurred only in the presence of Ca" . Intracellular lysosomal rupture was not associated with measurable degradation of total DNA, RNA, protein, or phospholipid or accelerated turnover of exogenous horseradish peroxidase . Pretreatment with promethazine (20 pg/ml) protected 80% of P388D, macrophages against silica toxicity although lysosomal rupture occurred in 60-70% of the cells. Intracellular lysosomal rupture was prevented in 80% of the cells by pretreatment with indomethacin (5 x 10 -5 M), yet 40-50% of the cells died after 3 h of exposure to 150 p,g silica in 1 .8 mM extracellular Ca" . The calcium ionophore A23187 also caused intracellular lysosomal rupture in 90-98% of the cells treated for 1 h in either the presence or absence of extracellular Ca t+ . With the addition of 1 .8 mM Ca 2+, 80% of the cells was killed after 3 h, whereas all of the cells remained viable in the absence ofCa". These experiments suggest that intracellular lysosomal rupture is not causally related to the cell death caused by silica or A23187 . Cell death is dependent on extracellular Ca 2+ and may be mediated by an influx of these ions across the plasma membrane permeability barrier damaged directly by exposure to these toxins .Lysosomes participate in the physiological turnover of cellular macromolecules (15), limited autophagy of cellular organelles, and storage of undegradable materials (13). At least 60 different enzymes capable of digesting nucleic acids, proteins, lipids, and carbohydrates (6) are contained in these membrane-bound organelles, separated from their potential substrates. Endogenous or exogenous substances enter the lysosome by fusion of autophagic (13) or endocytic vacuoles (34) with lysosomes. This confines hydrolytic processes to the lysosome and presumably prevents unregulated intracellular digestion (13) .In various pathological states, cell injury may be produced by either extracellular or intracellular release of lysosomal enzymes (16). Extracellular release of lysosomal enzymes ac-