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Neurodevelopmental Toxicity and Metabolism of the Flame Retardant, Tris (1,3-dichloro-2-propyl) PhosphateEPA Grant Number: FP917288
Title: Neurodevelopmental Toxicity and Metabolism of the Flame Retardant, Tris (1,3-dichloro-2-propyl) Phosphate
Investigators: Dishaw, Laura V
Institution: Duke University
EPA Project Officer: Cobbs-Green, Gladys M.
Project Period: September 1, 2011 through August 31, 2014
Project Amount: $126,000
RFA: STAR Graduate Fellowships (2011) RFA Text | Recipients Lists
Research Category: Academic Fellowships , Fellowship - Human Health: Public Health Sciences
Since the 2004 phase out of polybrominated diphenyl ethers (PBDEs), organophosphate flame retardants (OPFRs), particularly tris(1,3-dichloro- 2-propyl) phosphate (TDCPP), have been used increasingly to meet state and federal flammability standards. Like PBDEs, OPFRs are known to leach out of treated materials and TDCPP has been detected at levels equivalent to PBDEs in household dust. OPFRs are structurally similar to organophosphate pesticides, a class of known neurotoxicants, and children are predicted to have the highest exposure to flame retardants (FRs). The aim of this project is to assess whether exposure to TDCPP and other OPFRs may elicit adverse effects on the developing nervous system.Approach:
A combination of in vitro and in vivo approaches will be used. PC12 cells, a neuronotypic rat cell line that has been used extensively to evaluate the developmental neurotoxicity of organophosphate pesticides, were used to screen TDCPP and three similar OPFRs (tris 2,3-dibromo-2-propyl phosphate, TDBPP; tris 2-chloroethyl phosphate, TCEP; tris 1-chloro-2-propyl phosphate, TCPP) for effects on cellular replication, cell number, cell viability and phenotypic differentiation. A zebrafish model will be used to assess morphological, behavioral and histological changes following developmental and chronic dietary exposure to these same compounds. The effects of OPFRs will be compared to chlorpyrifos (CPF), a wellstudied organophosphate pesticide and known developmental neurotoxicant. Because the rates and pathways of metabolism are often integral to toxicity of a chemical, S9 liver fractions and primary hepatocytes also will be used to learn more about TDCPP metabolism in humans.Expected Results:
In the PC12 cell studies, it was found that exposure to an equimolar concentration of TDCPP resulted in deficits equivalent to or greater than that of CPF on measures of cellular replication and cell number, without affecting cell viability. TDCPP also altered the pattern of phenotypic differentiation, resulting in elevated expression of both the cholinergic and dopaminergic phenotypes. Subsequent comparisons of equimolar concentrations of TDBPP, TCEP and TCPP found equivalent effects on cell number. Like TDCPP, TDBPP elicited an increase in expression of both the cholinergic and dopaminergic phenotypes while TCEP and TCPP exposure resulted in an increase in cholinergic expression without affecting the dopaminergic phenotype. These data suggest that the extent of halogenation rather than the type of halogen substituent is a critical determinant of the effects on phenotypic differentiation. It is expected that developmental exposure of zebrafish to high concentrations of OPFRs will result in increased rates of mortality and malformations while lower concentrations will induce histological and behavioral abnormalities that are indicative of more subtle, neurotoxic effects. Chronic dietary exposure to TDCPP is predicted to result in accumulation of the parent compound and metabolites in the tissues of zebrafish and induce histological changes in the brain. The S9 liver fraction and hepatocyte studies will be used to identify important metabolites and metabolic pathways of TDCPP in humans.
Potential to Further Environmental / Human Health Protection
Due to the potential for neurotoxicity and models suggesting that infants and young children have the highest exposure to FR chemicals, there is an urgent need to assess the potential for TDCPP and other OPFRs to elicit adverse effects on the developing nervous system. Furthermore, identification of the pathways and products of TDCPP metabolism can be used to estimate the rate at which this compound is eliminated from the body and determine biomarkers of exposure in the human population. The results of this proposal can provide regulatory agencies with data needed to make accurate risk assessments and guide decisions regarding the continued use of TDCPP and similar FR chemicals.Supplemental Keywords:
flame retardant, organophosphate, developmental neurotoxicity