Strategies for testing the "irritation-signaling" model for chronic lung effects of fine acid particles

The "irritation signaling" model proposed that a long term contribution to chronic bronchitis might result from the repeated delivery of "signals" resulting from temporary localized acidification of the bronchial epithelium by the action of individual particles. This led to a prediction that the effectiveness of particles in inducing changes in mucus secreting cell numbers/types should depend on the number of particles deposited that contained a particular amount of acid--implying that particles below a certain size cutoff (and therefore lacking a minimum amount of acid) should be ineffective; and that particle potency per unit weight should be greatest at the cutoff and decline strongly above the cutoff. Since the development of this hypothesis both epidemiological observations and some experimental studies have tended to reinforce the notion that acid particles can make a contribution to relatively long lasting bronchitic-like changes, and enhance the desirability of more direct testing of the model. In this paper we develop a general theoretical framework for the contributions of environmental agents to chronic obstructive lung disease, and a series of alternative hypotheses against which the predictions of the "irritant signaling" model can be compared. Based on this, we suggest a research program that could be used to further develop and test the model and reasonable alternatives.