Asthma is the most common chronic disease of children. The etiology is not clear, but recent studies suggest that traffic-related particulate air pollution may contribute to the occurrence of childhood asthma and asthma- related bronchitic symptoms. Respirable particulate matter (PM) produces oxidative stress and acute inflammatory and allergic affects characteristic of asthma, but there has been little study of how these effects may lead chronically to the development of disease. A better understanding of which specific PM-induced biological effects result in asthma could lead to targeted clinical interventions and to new prevention strategies focused on the biological activity of PM. We propose a new approach to population studies of complex mixtures of air pollution that will assess exposure based on the in vitro effects of PM on key biological pathways and examine the relationship to the development of chronic disease. These pathways include inflammation, characterized by PM-induced cytokines (IL-8, GM-CSF, and IL-12), allergy (IgE response and release of histamine) and oxidative stress (reactive oxygen species production, GST activity and Phase II enzyme induction). We will also investigate genetic susceptibility based on the change in PM-induced biological activity in cells expressing GSTM1 and in cells with GSTM1 expression reduced using siRNA. We selected this gene as a prototype for our research approach because it has a common null genotype that increases the risk of asthma associated with oxidant PM exposure. We will use the in vitro toxicological assays to predict the risk of asthma and assess susceptibility associated with GSTM1 genotype. Our ongoing prospective cohort study of air pollution, genetics and respiratory disease among 3372 children in the southern California Children's Health Study provides an opportunity to use the new approach to evaluate whether: 1) asthma incidence and bronchitic exacerbation are associated with the in vitro ability of PM to induce pro- oxidant, inflammatory and allergic effects; and 2) susceptibility to health effects of PM-induced biological activity is influenced by in vitro GSTM1 expression and by participants' GSTM1 genotype. The in vitro biological responses to PM less than 2.5 5m in aerodynamic diameter will be measured along with gaseous oxidant co-pollutants (NOx and ozone) at community monitors, schools and a sample of homes in each of the eight study communities. Results will be integrated in the analyses using an innovative hierarchical modeling strategy to predict variation in particle biological activity related to traffic within communities and across study communities representing the range of ambient PM exposure in southern California. Each biological exposure index, which will be specific for study participants' GSTM1 genotype, will be assigned to the entire cohort and will be used to predict asthma and bronchitic symptoms. The study has the potential to fill important gaps in our understanding of the [unreadable] [unreadable] [unreadable] role of particulate air pollution in the development of childhood respiratory disease. PUBLIC HEALTH RELEVANCE This new approach to exposure assessment has the potential to provide better estimates of asthma risk and susceptibility due to exposure to particulate air pollution. This information will be useful for risk assessment and could lead to new regulatory and monitoring approaches for controlling the health hazards of air pollution. [unreadable] [unreadable] [unreadable]