PMID- 30312655 OWN - NLM STAT- MEDLINE DCOM- 20191119 LR - 20191119 IS - 1872-9738 (Electronic) IS - 0892-0362 (Linking) VI - 70 DP - 2018 Nov-Dec TI - Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance. PG - 40-50 LID - S0892-0362(18)30101-6 [pii] LID - 10.1016/j.ntt.2018.10.002 [doi] AB - Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment. We utilized zebrafish embryos to assess developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity, of eight replacement 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]) and two BFRs (3,3',5,5'- tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). To determine potential effects on teratogenicity, embryos were exposed to flame retardants (FRs) at 4 h post fertilization (hpf) to 4 days post fertilization (dpf) and morphological alterations and corresponding survival were evaluated at 2 and 4 dpf. Internal concentrations were measured in larvae used in this assay by liquid chromatography-mass spectrometry. Locomotor activity was assessed in larvae treated for 48 h (from 3 dpf to 5 dpf), followed by hepatotoxicity evaluation. Finally, alterations in heart rate and rhythmicity were assessed to determine cardiotoxicity in 48 hpf embryos exposed to compounds for 3 h. Results suggest that several OPFRs (BPDP, EHDP; IPP, TMPP; TPHP and TDCIPP) produced adverse effects in multiple target organs at concentrations comparable to the two BFRs. As these OPFRs have the capacity to disrupt an integrated vertebrate model, they potentially have the capacity to affect mammalian biology. Then, we compared the lowest effective levels (LEL) in zebrafish with estimated or measured human plasma concentrations using biomonitoring data (human plasma, breast milk, handwipe samples and house dust) and a high throughput toxicokinetic (HTTK) model. Results indicate that for some compounds, the nominal LELs were within the range of human exposures, while internal LELs in zebrafish are above internal exposures in humans. These findings demonstrate the value of the zebrafish model as a relevant screening tool and support the need for further hazard characterization of the OPFRs. CI - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Alzualde, Ainhoa AU - Alzualde A AD - BIOBIDE, Donostia - San Sebastian, Gipuzkoa, Spain. FAU - Behl, Mamta AU - Behl M AD - Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States of America. FAU - Sipes, Nisha S AU - Sipes NS AD - Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States of America. FAU - Hsieh, Jui-Hua AU - Hsieh JH AD - Kelly Government Solutions, Research Triangle Park, NC, United States of America. FAU - Alday, Aintzane AU - Alday A AD - BIOBIDE, Donostia - San Sebastian, Gipuzkoa, Spain. FAU - Tice, Raymond R AU - Tice RR AD - Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States of America. FAU - Paules, Richard S AU - Paules RS AD - Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States of America. FAU - Muriana, Arantza AU - Muriana A AD - BIOBIDE, Donostia - San Sebastian, Gipuzkoa, Spain. FAU - Quevedo, Celia AU - Quevedo C AD - BIOBIDE, Donostia - San Sebastian, Gipuzkoa, Spain. Electronic address: quevedo@biobide.es. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20181009 PL - United States TA - Neurotoxicol Teratol JT - Neurotoxicology and teratology JID - 8709538 RN - 0 (Flame Retardants) RN - 0 (Organophosphates) RN - 0 (Organophosphorus Compounds) RN - YZE19Z66EA (triphenyl phosphate) RN - Z1E45TMW1Z (trimethyl phosphate) SB - IM MH - Animals MH - Cardiotoxicity/etiology MH - Embryonic Development/*drug effects MH - Flame Retardants/*toxicity MH - Humans MH - Neurotoxicity Syndromes/etiology MH - Organophosphates/pharmacology/*toxicity MH - Organophosphorus Compounds/*toxicity MH - Zebrafish OTO - NOTNLM OT - Cardiotoxicity OT - Developmental toxicity OT - Flame retardants OT - Hepatotoxicity OT - Internal concentration OT - Neurotoxicity OT - Zebrafish EDAT- 2018/10/13 06:00 MHDA- 2019/11/20 06:00 CRDT- 2018/10/13 06:00 PHST- 2018/07/27 00:00 [received] PHST- 2018/10/03 00:00 [revised] PHST- 2018/10/08 00:00 [accepted] PHST- 2018/10/13 06:00 [pubmed] PHST- 2019/11/20 06:00 [medline] PHST- 2018/10/13 06:00 [entrez] AID - S0892-0362(18)30101-6 [pii] AID - 10.1016/j.ntt.2018.10.002 [doi] PST - ppublish SO - Neurotoxicol Teratol. 2018 Nov-Dec;70:40-50. doi: 10.1016/j.ntt.2018.10.002. Epub 2018 Oct 9.