Project Summary/Abstract Rising worldwide ambient particulate matter (PM) concentrations and increasing occurrences of high volume exposures via dust storms or catastrophic events have put the general public at risk. While there are studies examining the health implications associated with high and low concentration PM exposures, to date there has not been an extensive study examining both exposures concomitantly. One of the most notorious large scale exposures occurred on September 11, 2001. Nearly 3,000 people perished in the attacks, 87% of which were in New York City (NYC) alone. Thirteen years later people in and around the NYC area are still suffering and dying from illnesses likely caused by dust and debris exposure from the collapse of the World Trade Center (WTC). While the etiologies of some illnesses are known, due to the unique set of circumstances and confounding effects, the definitive cause of many are not. What is known is that hundreds of thousands of people were exposed to a high dose of PM in the form of WTC dust. This high dose was then followed by months of chronic exposure to lower levels of WTC dust, cutting fumes, diesel exhaust, and ambient PM pollution. A comprehensive in vivo exposure study is proposed utilizing a mouse model. A moderately susceptible wild type strain, FVB/NJ, will be used in the exposures to better differentiate between groups while also generating realistic inflammatory responses. The exposures themselves can be broken down into three major groups: 1) high acute exposure (HAE), 2) HAE followed by subchronic exposures (SCE), and 3) SCE. For comparison, the HAE be performed with either WTC dust or concentrated ambient particles (CAPs). The SCE will be a lower concentration of WTC dust, CAPs, or diesel exhaust particles (DEP). The SCE will occur over a range of time periods (1 ? 28 days) in order to fully understand the short and long term effects of the dual exposures. The three main exposure groups will allow for the origin of inflammation to be understood by isolating components. This systematic approach will also help determine if the tandem exposures generate inflammation beyond mere additive effects. Furthermore, harvested tissue samples will also be used to determine the effects of the subchronic exposures on WTC dust distribution. Human tissue samples obtained from the World Trade Center Health Registry will be compared with different in vivo tissue samples to determine if there are any correlations between metal distribution, associations, and/or structural states using a synchrotron light source. In summary, the etiologies of the chronic illnesses related to WTC dust exposure will be investigated. This incident will also be used as a case study examining the hazards associated with subchronic particle exposures following a major acute particle exposure event. A translational model of in vivo mouse exposures will be compared to published epidemiological data and available human tissue samples.