Lung deposition dose of black carbon as a driver of health Disparities - 1 Particulate matter emitted through incomplete combustion of fossil fuels and biomass, known as combustion- 2 emitted particulate matter (CE-PM), has emerged as a critical public health and climate change issue in the 3 United States (US) and world-wide. Despite the implementation of The Clean Air Act in the 1970s, which led to 4 a persistent reduction in ambient PM2.5 levels in the US, racial-ethnic disparities in PM exposure remain 5 significant. People of color (POC), on average, experience disproportionate exposure to ambient PM2.5, with 6 Black Americans experiencing the highest levels of PM2.5 exposure both nation-wide (by 34% higher than White 7 Americans) and in most states. Moreover, the majority (>75%) of PM2.5 that POC breathe is from emission 8 sources disproportionately affecting POC. This pattern is consistent across exposure levels, even in POC with 9 optimal social determinants of health status (SDOH). The literature also reports that Black Americans reside 10 near emission sources such as traffic and industry due to a legacy of racist housing policies, and thus may be 11 exposed to more toxic PM, i.e., fresh combustion particles. A significant knowledge gap remains regarding 12 whether racial-ethnic disparity in ambient PM2.5 exposure can translate to higher lung deposition dose of black 13 carbon in Black versus White Americans and whether Black Americans are exposed to PM with stronger pro- 14 inflammatory potency than White Americans. We hypothesized that not only do Black Americans have higher 15 PM exposure, but that they are also exposed to more toxic PM due to the proximity of their neighborhoods to 16 traffic and industry. Macrophage carbon load (MaCL) is a novel sputum cytology-based method that quantifies 17 black carbon particles engulfed by the macrophages and reflects the lung dose of total CE-PM exposure at an 18 individual level over the past several months. We have successfully developed an innovative Machine-Learning 19 algorithm for Engulfed cArbon Particles (MacLEAP) that automates the scoring process of MaCL assay, and is 20 validated, high-throughput, and scorer-independent. This application will utilize biospecimens (sputum and blood) 21 from the Subpopulations and Intermediate Markers in COPD Study (SPIROMICS), a NHLBI-funded 22 observational study, which enrolled a geographically diverse cohort consisting predominantly of Black and White 23 Americans. We have identified 139 Black and White Americans each that are frequency-matched by age (± 10 24 years), sex (male and female), and stratum (non-smokers, smokers without airflow obstruction, smokers with 25 mild/moderate COPD, and smokers with severe COPD). Specific Aim 1 will assess whether Black Americans 26 have higher lung deposition dose of black carbon compared to White Americans using MaCL assay. Specific 27 Aim 2 will compare pro-inflammatory potency of PM exposures between Black and White Americans based on 28 slopes of the dose-response relationship between MaCL and pulmonary and systemic inflammation. Successful 29 completion of this study will greatly advance our understanding of racial-ethnic disparities in PM exposure and 30 toxicity, which is critical for identifying drivers of racial-ethnic disparities in PM induced health effects.