Noyes, P.D., Haggard, D.E., Gonnerman, G.D., Tanguay, R.L. (2015) Advanced morphological-behavioral test platform reveals neurodevelopmental defects in embryonic zebrafish exposed to comprehensive suite of halogenated and organophosphate flame retardants. Toxicological sciences : an official journal of the Society of Toxicology. 145(1):177-95.
Sharp increases in the use of flammable plastics and electronic devices coupled with stricter fire safety requirements have promoted the heavy use of flame retardant chemicals. While 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 non-mammalian 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 and several of their known metabolites. Zebrafish were exposed to flame retardants from 6-120 hours post fertilization (hpf) across concentrations spanning four orders of magnitude (e.g., 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 two 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 (mITP) and the brominated-bisphenol-A analog tetrabromobisphenol-A (TBBPA) 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 non-lethal 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.