Current epidemiologic research on the health effects of environmental toxins is limited by available methods of linking exposure to disease. The goal of this proposal is to investigate models with which the association of non-malignant respiratory disease risks and toxic chemicals can be studied. It continues development of a systematic approach to the construction and evaluation of epidemiologic models. A guiding principle of this work is that epidemiologic models should reflect, in the complexity of their response to the toxin and their temporal behavior, the biologic processes that underlie the hypothesized associations between exposure and response that are the focus of epidemiologic study. The approach being developed is based on the pathophysiologic mechanisms of toxic injury; taking account of the complex, non-linear nature of most toxic processes. Drawing on the principles of compartmental pharmacologic modeling, pathophysiologic processes are translated into a mathematical model which can capture the hypothesized exposure-response relationship, the temporal dynamics of deposition and clearance of the toxin, and of damage and repair of the target tissue. It is hypothesized that when disease processes such as immune mediation and tissue repair are incorporated into epidemiologic models, more accurate predictions of exposure-response associations will be possible. Models are developed and applied to several existing data sets as well as to new data collected prospectively on subjects during their first exposure to irritant and sensitizing aerosols. Results are compared to those obtained by more conventional methods. Studies will focus on the bronchoconstrictive effects of: ozone, irritating dusts generated in the processing of borates and limestone, and of welding fume.
