Developmental toxicity of organophosphate-based flame retardants

Access restricted to the OSU CommunityThe commercial polybrominated diphenyl ether (PBDE) mixture known as PentaBDE was once the primary flame retardant (FR) used in the US to comply with California's Technical Bulletin 117 (TB117) - a mandated flammability standard for polyurethane foam within upholstered furniture and baby products. In 2004, due to concerns about persistence, bioaccumulation, and toxicity, PentaBDE was voluntarily phased out, prompting an industry-wide shift toward the use of alternative flame retardant formulations containing at least one of the two major classes of organophosphate-based flame retardants (OPFRs) - chlorinated phosphate esters (CPEs) and aryl phosphate esters (APEs). Due to rapid adoption as PentaBDE replacements, organophosphate-based flame retardants (OPFRs) have been detected at concentrations comparable to and, in some cases, higher than total PBDE concentrations in household dust, suggesting that chronic human exposure to these alternative flame retardants following leaching from treated products is common within the United States. Despite the need for a better understanding of the potential developmental effects of OPFRs (since infants and children tend to (1) ingest more house dust than adults due to crawling and mouthing behaviors and (2) be exposed up to five times the acceptable daily OPFR intake level due to use in residential furniture), most studies to date have focused on the genotoxicity or neurotoxicity of OPFRs within adult animals. Using zebrafish as an animal model, the objective of these studies was to begin uncovering the mechanisms of developmental toxicity for OPFRs commonly detected within indoor environments. Our results demonstrate that the two major classes of OPFRs - CPEs and APEs - exhibit distinct mechanisms of toxicity during zebrafish embryogenesis. Specifically, exposure to the high-production volume CPE tris(1,3- dichloro-2-propyl) phosphate (TDCPP) delayed zygotic genome remethylation during early embryogenesis, while exposure to triphenyl phosphate (TPP) and monoisopropylated triaryl phosphate (Mono-ITP) - two APEs that account for 49% of Firemaster 550, a major PentaBDE replacement - resulted in severe cardiac abnormalities during early vertebrate development. Overall, these results are the first to show early developmental toxicity of widely used and detected OPFRs