Project Summary There is an increased thyroid cancer incidence reported in the World Trade Center (WTC) first responder's cohorts and no evidence of surveillance or physician bias as the reason for this increase was found. Moreover, results from previous studies suggested that inflammation in distant organs following respiratory WTC dust exposure might be the common pathway driving this increased cancer risk. However, no research to date has investigated the potential accumulation of WTC dust components and/or their metabolites in distant organs, including the thyroid, as a potential (additional) driver of inflammation and carcinogenesis in WTC-exposed populations. WTC dust analyses identified a variety of different particles, including metals, with unknown carcinogenic effect on the thyroid. Using untargeted metabolomics of formalin-fixed paraffin- embedded (FFPE) thyroid cancer tissue samples, we aim to identify chemical profiles and potential pathways of interest reflecting a potential mechanistic action comparing 50 WTC- exposed thyroid cancer samples with 50 non-WTC exposed thyroid cancer samples and 50 benign thyroid cancer tissue (aim 1). We will additionally perform a subgroup analysis using a novel approach to measure the distribution of metals in thyroid tissue and the spatial association with markers of local inflammation in fresh frozen tissue comparing 5 WTC-exposed thyroid cancer samples with 5 non-WTC exposed thyroid cancer samples and 5 benign thyroid cancer tissue (aim 2). This study would be the first in-depth study to investigate the presence of WTC dust components and/or their metabolites in human thyroid cancer tissue and the potential association with chronic tissue inflammation, which would provide critical information about a potential pathway driving the increased thyroid cancer occurrence in the WTC-exposed population. The proposed methods can easily be transposed to other solid cancers with increased risk in the WTC population, including prostate cancer, as well as to population studies investigating environmental pollutants as risk factor for the global thyroid cancer increase. Insight in the presence of environmental pollutants and their metabolites and potentially associated local inflammation in thyroid cancer tissue as driving factors for carcinogenesis would shape future epidemiological environmental cancer research.