title: Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity.
abstract: Due to their toxicity and persistence in the environment, brominated flame retardants (BFRs) are being phased out of commercial use, leading to the increased use of alternative chemicals such as the organophosphorus flame retardants (OPFRs). There is, however, limited information on the potential health effects of OPFRs. Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity. In response, we evaluated a set of OPFRs (triphenyl phosphate [TPHP]), isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], (tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl)phosphate [TCEP]) in a battery of cell-based in vitro assays and alternative model organisms and compared the results to those obtained for two classical BFRs (3,3',5,5'-tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). The assays used evaluated the effects of chemicals on the differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of nematode (Caenorhabditis elegans) and zebrafish (Danio rerio). All assays were performed in a concentration-response format, allowing for the determination of the point of departure (POD: the lowest concentration where a chemically-induced response exceeds background noise). The majority of OPFRs (8/9) were active in multiple assays in the range of 1-10 μM, most of which had comparable activity to the BFRs TBBPA and BDE-47. TCEP was negative in all assays. The results indicate that the replacement OPFRs, with the exception of TCEP, showed comparable activity to the two BFRs in the assays tested. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard of some of these OPFR compounds.
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address: behlmv@niehs.nih.gov.
authors.forename: Mamta
authors.initials: M
authors.lastname: Behl
authors.affiliation: Kelly Government Solutions, RTP, NC, USA.
authors.forename: Jui-Hua
authors.initials: JH
authors.lastname: Hsieh
authors.affiliation: Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
authors.affiliation: Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Mundy
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Rice
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Windy A
authors.initials: WA
authors.lastname: Boyd
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
authors.affiliation: Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC, USA.
authors.forename: E Sidney
authors.initials: ES
authors.lastname: Hunter
authors.affiliation: Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Jarema
authors.affiliation: Integrated Systems Toxicology Division, Office of Research and Development, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, RTP, NC, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Padilla
authors.affiliation: Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D017173:Caenorhabditis elegans; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D047108:Embryonic Development / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000187:drug effects*; D005411:Flame Retardants / Q000633:toxicity*; D006801:Humans; D051379:Mice; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D015027:Zebrafish
chemical_list: D005411:Flame Retardants; D009943:Organophosphorus Compounds
keywords: Caenorhabditis elegans; Flame retardants; developmental toxicity; embryonic stem cells; neurotoxicity; zebrafish