To evaluate the in vivo versus in vitro paradoxical effects of marijuana and tobacco smoke on pulmonary defenses, the responses to smoke constituents were assessed with an alveolar macrophage tissue culture bioassay. A dose-response impairment of macrophage bactericidal activity was associated with water-soluble, gas-phase constituents. A model airway surface was constructed to examine the behavior of specific gas-phase constituents removed as they passed over wetted surfaces simulating the characteristics of the human respiratory system. Chemical analyses in the bioassay flask and in the model airway were compared. Gas-phase cytotoxins were measured after passage over wetted surface areas analogous to the trachea between the larynx and second-order bronchus. A wetted surface comparable to only 5% of the human airway, or less than 0.05% of the gas-exchanging surface of the entire lung, was capable of complete detoxification of the highly water-soluble gas-phase cytotoxins. In conclusion, gas-phase cytotoxins demonstrable by in vitro bioassays may have no cytotoxic potential when inhaled by humans.