PROJECT SUMMARY Flammability requirements are set for consumer products by state and federal agencies, resulting in the addition of flame retardant chemicals to furniture, textiles, electronics, and other products found ubiquitously in homes around the world. The production volumes of organophosphate flame retardants (OPES) have drastically increased in recent years due to the phase-out of the neurotoxic polybrominated diphenyl ether (PBDE) flame retardant chemicals. The metabolites of OPES are detectable in biological samples of 77-90% of U.S. adults, and exposure occurs mainly through accidental dust ingestion. There is a startling lack of research into the health consequences of exposure to these replacement flame retardants, but they have been linked to neurobehavioral toxicity and thyroid hormone disruption in animals. Tight thyroid hormone regulation during gestation and early childhood is essential for normal brain development, and others have speculated that thyroid disruption may be one mechanism by which OPEs cause neurotoxicity. There is very little research on the consequences of OPE exposure in humans, and none in children or longitudinal cohorts. We intend to fill this knowledge gap with the proposed work. Our overarching hypothesis is that exposure to OPEs during gestation and early childhood is associated with thyroid hormone disruption, decreased child intelligence, and increased ADHD behaviors. In aim 1, we will measure the association between exposure to OPEs at several time points and thyroid function in children. In aim 2, we will investigate the link between OPE exposure and child intelligence and ADHD symptoms, including a mediation analysis to determine whether thyroid function lies on this causal pathway. Finally, aim 3 will involve a mixtures analysis of exposure to a combination of OPEs, PBDEs, and lead and the outcome of child intelligence. To accomplish these aims, we will utilize a well-established prospective pregnancy and birth cohort in the Greater Cincinnati area—the HOME Study (n=410 births with follow-up to 12 years of age). We will analyze stored household dust and urine samples from pregnant women and their children to measure exposure to OPEs at up to nine time-points. We will also examine previously measured thyroid hormone levels from maternal blood, cord blood, and child blood and draw on an extensive battery of child neurobehavioral data. For the chemical mixtures analysis, serum PBDE concentrations and blood lead levels have already been measured from maternal and child samples, and we will employ five different analytical methods to explore synergistic interactions and joint effects on the outcome of child intelligence. This project will be the among the first to systematically explore the relationship between pre- and post-natal replacement flame retardant exposure, TH levels, and neurobehavior in an established birth cohort of children. The results of our chemical mixtures analysis will give this fie...