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Utilizing alternative developmental and neurotoxicity screening methods to prioritize compounds for further mammalian testing
Citation:
Behl, M., J. Hsieh, Tim Shafer, W. Mundy, J. Rice, W. Boyd, J. Freedman, S. Hunter, K. Jarema, S. Padilla, AND R. Tice. Utilizing alternative developmental and neurotoxicity screening methods to prioritize compounds for further mammalian testing. Future Tox III, Arlington, VA, November 19 - 20, 2015.
Impact/Purpose:
Many of the organophosphate chemicals showed developmental or acute neurobehavioral alterations at low micromolar concentrations. Using the data presented in this paper, interested parties may be able to make more informed choices about which chemicals to concentrate on for further testing.
Description:
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). Due to the structural similarity of the OPFRs to organophosphorus insecticides, there is concern regarding developmental toxicity and neurotoxicity; however, there is limited information on their potential health effects. A set of OPFRs were evaluated (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; results were compared to two classical BFRs (3,3',5,5'-tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). The assays included differentiation of mouse embryonic stem cells, the proliferation and growth of human neural stem cells, rat neuronal growth and network activity, and development of C. elegans and zebrafish.All assays were performed in a concentration-response format, allowing for the determination of a benchmark concentration (BMC: 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. Based on these results, more comprehensive studies are warranted to further characterize the potential hazard of some of these OPFR compounds