Noyes Pamela D, Haggard Derik E, Gonnerman Greg D, Tanguay Robert L
Department of Environmental & Molecular Toxicology, Environmental Health Sciences Center, and the Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331.
Department of Environmental & Molecular Toxicology, Environmental Health Sciences Center, and the Sinnhuber Aquatic Research Laboratory, Oregon State University, Corvallis, Oregon 97331
Toxicol Sci. 2015 May;145(1):177-95. doi: 10.1093/toxsci/kfv044. Epub 2015 Feb 23.
The increased use of flammable plastics and electronic devices along with stricter fire safety standards has led to the heavy use of flame retardant chemicals in many consumer, commercial, and industrial products. Although flame retardant use has increased, a great deal of uncertainty surrounds their safety with some evidence showing toxicity and risk to human and environmental health. Recent efforts have focused on designing high-throughput biological platforms with nonmammalian models to evaluate and prioritize chemicals with limited hazard information. To complement these efforts, this study used a new morphological and behavioral testing platform with embryonic zebrafish to characterize the developmental toxicity of 44 halogenated and organophosphate flame retardants, including several of their known metabolites. Zebrafish were exposed to flame retardants from 6 to 120 h post fertilization (hpf) across concentrations spanning 4 orders of magnitude (eg, 6.4 nM to 64 µM). Flame retardant effects on survival and development were evaluated at 24 and 120 hpf, and neurobehavioral changes were measured using 2 photomotor response (PMR) assays. Compared to controls, 93% (41/44) of flame retardants studied elicited adverse effects among one or more of the bioassays and concentrations tested with the aryl phosphate ester (APE)-based mono-isopropylated triaryl phosphate and the brominated-bisphenol-A analog tetrabromobisphenol-A producing the greatest array of malformations. Hierarchical clustering showed that APE flame retardants with isopropyl, butyl, and cresyl substituents on phenyl rings clustered tightly and were particularly potent. Both PMR assays were highly predictive of morphological defects supporting their use as nonlethal means of evaluating teratogenicity that could allow for additional evaluations of long-term or delayed effects in older animals. Taken together, evidence presented here indicates that zebrafish neurodevelopment is highly sensitive to many flame retardants currently in use and can be used to understand potential vulnerabilities to human health.
易燃塑料和电子设备的使用增加,以及更严格的消防安全标准,导致许多消费品、商业产品和工业产品大量使用阻燃化学品。尽管阻燃剂的使用有所增加,但围绕其安全性仍存在诸多不确定性,一些证据表明其对人类和环境健康具有毒性和风险。最近的努力集中在设计具有非哺乳动物模型的高通量生物平台,以评估危害信息有限的化学品并对其进行优先级排序。为补充这些努力,本研究使用了一个新的形态学和行为测试平台,以斑马鱼胚胎来表征44种卤代和有机磷酸酯阻燃剂及其几种已知代谢物的发育毒性。斑马鱼在受精后6至120小时(hpf)暴露于阻燃剂,浓度范围跨越4个数量级(例如,6.4 nM至64 μM)。在24和120 hpf评估阻燃剂对生存和发育的影响,并使用两种光运动反应(PMR)试验测量神经行为变化。与对照组相比,在所研究的阻燃剂中,93%(41/44)在一种或多种生物测定以及测试浓度下引发了不良反应,其中基于芳基磷酸酯(APE)的单异丙基化三芳基磷酸酯和溴化双酚A类似物四溴双酚A产生的畸形种类最多。层次聚类表明,在苯环上带有异丙基、丁基和甲酚取代基的APE阻燃剂紧密聚集,且特别有效。两种PMR试验都能高度预测形态缺陷,支持将其用作评估致畸性的非致死手段,这可以对老年动物的长期或延迟影响进行额外评估。综上所述,此处提供的证据表明斑马鱼神经发育对目前使用的许多阻燃剂高度敏感,可用于了解对人类健康的潜在易感性。