Evaluating environmental metals exposure on risk of LCH

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PROJECT SUMMARY Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by an upfront chemotherapy failure rate of 50%, leading to disease progression that results in considerable short-term morbidity and significant late effects. LCH presents with a wide spectrum of symptoms, from self-resolving single-organ lesions to potentially fatal disseminated multi-organ disease. LCH occurs throughout life, with a median age at diagnosis of 30 months, and incidence of 4-8 cases per million children <15 years of age. While the somatic mutational drivers for LCH have been elucidated, risk factors related to LCH susceptibility are not well understood. In our R01, we are investigating the genetic mechanisms underlying the pathogenesis of LCH and noted that the age-standardized incidence rates for LCH is higher among Hispanic children (0-19 years old) compared to non-Hispanics. We also noted that genetic variation with SMAD6 may contribute to the observed ethnic disparity in incidence of LCH. However, we cannot rule out the potential role of environmental factors on susceptibility as Hispanics are also disproportionately exposed to environmental toxicants. In fact, there is some epidemiologic evidence that exposure to certain environmental factors, including metals, may contribute to risk of LCH. Several metals, including arsenic, cadmium, chromium, and nickel, are classified as carcinogenic by the International Agency for Research on Cancer. Prior studies examining risk of metal exposure and LCH were based on parental occupational exposure, which would misclassify those residentially exposed, and did not specify the timing of exposure (i.e., prenatal or postnatal). To overcome some of these limitations, studies of childhood leukemia have linked residential addresses at birth or diagnosis to sources of pollutants and evaluated risk. However, no studies have leveraged geospatial information in relation to risk of LCH. Furthermore, another limitation of self-reported or linkage to geospatial data is that the studies lack objective measurements of specific metals. Deciduous or primary teeth are a novel, non-invasive, and readily accessible exposure assessment matrix that can provide objective measurements on pre- and post-natal uptake of environmental toxicants, including metals, and have not been adopted in studies of LCH. Additionally, data from primary teeth have not been well characterized in relation to geospatial proximity to environmental sources of toxicants. Our overall objective is to apply novel and underutilized exposure assessment methods to our studies of LCH. The goal of this supplemental application to our funded R01 is to conduct a pilot study to assess the feasibility of obtaining primary teeth as novel exposure assessment matrix in studies of LCH and linking addresses to geospatial data. We hypothesize that primary teeth will overcome the exposure assessment limitations of prior studies and be an excellent exposure assessment method to expand to a larger study investigating environmental risk factors of LCH.