PROJECT SUMMARY/ABSTRACT Per- and polyfluoroalkyl substances (PFAS) have been used in many manufacturing and commercial products in recent decades, resulting in widespread and persistent contamination despite the phasing out of early compounds such as PFOS and PFOA. Routes of PFAS exposure to humans vary by age; while exposures in infants and children are commonly from breastfeeding and ingestion of settled dust, adolescents and adults are primarily exposed through food and water. PFAS have been associated with several adverse health outcomes, including cancer in adults. Despite several reports of childhood cancer clusters in PFAS-contaminated areas, and potentially higher body burdens in children compared to adults, no studies have systematically assessed cancer risk in children, due, in part to the relative rarity of childhood cancer. We propose to conduct the first study of PFAS and cancer in children, by integrating the expertise of investigators from four institutions, forming a transdisciplinary virtual consortium with expertise in pediatric and cancer epidemiology, and environmental engineering and health sciences. Using innovative methodology, this virtual consortium will characterize PFAS from the most relevant routes of exposure by examining PFAS in drinking water (Aim 1), newborn and pregnancy blood samples (Aim 2), and household dust (Aim 3) during vulnerable exposure windows from pregnancy through early childhood, and subsequent risk of developing childhood cancer. We will focus on cancers that have been reported previously in communities and groups known to have high exposures to PFAS, such as leukemia, rhabdomyosarcoma, lymphoma, and cancers of the brain, central nervous system, kidney, testis, and thyroid. We will leverage two existing California childhood cancer studies with complementary designs offering large number of childhood cancer cases and controls with residential information, and with access to blood and dust samples for subsets. PFAS water exposure assessment, we will use a Bayesian pharmacokinetic calibration approach that combines measured drinking water concentrations with measured serum biomarkers to provide improved exposure estimates. We will also combine targeted and non-targeted mass spectrometric strategies to measure PFAS in blood and dust samples. There will be synergy between the three research aims by overlapping study participants (Aims 1 and 2), coordinating laboratory analyses (Aims 2 and 3) and statistical analyses (Aims 1, 2, 3), and by paying special attention to leukemia--the most common childhood cancer (Aims 1, 2, 3). The ViCTER Consortium will be supported by an Administrative and Scientific Oversight Core to coordinate and integrate resources and activities of the three research aims. With our unique resources, novel methods, and complementary expertise, this proposal responds to the urgent need of assessing population cancer risk to children related to PFAS.

PROJECT NARRATIVE Per- and polyfluoroalkyl substances (PFAS) have been used in many manufacturing and commercial products in recent decades, resulting in widespread and persistent contamination of the environment. Despite potentially higher body burdens in children, no previous epidemiologic studies have systematically assessed cancer risk associated with PFAS exposures in this age group. The proposed transdisciplinary study will fill major gaps in knowledge about PFAS routes of exposure during pregnancy and early life, and their subsequent impact on cancer risk in children.