Swelling of epithelial cells and reduction of ciliary activity in mouse trachea organ culture occurred after incubation for 4 h with a rather low concentration of cadmium acetate (10 microM). Specific inhibitors of ion transport (Na+, K+, Cl-) such as furosemide, amiloride and ouabain did not mimic, abolish or increase the toxic effects induced by cadmium acetate. Exposure to cadmium acetate had no significant effect on electrolyte uptake (22Na+ and 86Rb+). These results suggest that the swelling of epithelial cells induced by cadmium acetate is not due to an osmotic swelling from an accumulation of electrolytes. Ba2+, known to have several biological properties in common with Ca2+, and to influence basolateral K+ flux, counteracted the toxic effects of cadmium acetate, whereas a more rapid and extensive swelling occurred with cadmium acetate in a medium without Ca2+. No effect on the uptake of 109Cd2+ was found with barium chloride, whereas in a medium without Ca2+ the Cd2+ uptake increased by 47%. Trifluoperazine (100 microM), a drug which in vitro binds tightly to calmodulin, imitated the toxic effects of 10 microM cadmium acetate. The combination of 10 microM cadmium acetate and 100 microM trifluoperazine resulted in an additive toxic effect. A possible mechanism for the cadmium acetate-induced swelling and inhibition of ciliary activity could, thus, be a disturbance of the regulatory activity of calmodulin.