Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for teratogenicity, behavior, cardiotoxicity, and hepatotoxicity

Screening for neurotoxic potential of 15 flame retardants using freshwater planarians

“…Moreover, lethality suggests overt systemic toxicity at these concentrations which may have masked effects at more specific endpoint readouts. Given the overt toxicity at lethal concentrations, many labs only evaluate more sensitive morphological or behavioral effects at sublethal concentrations, disregarding effects at lethal concentrations (Alzualde et al, 2018;Jarema et al, 2015;Truong et al, 2014). All together, these data indicate that different number of replicates (from 3-6) yield very similar results, validating that our current screening strategy using 3 replicates is able to robustly identify chemical bioactivity and different toxicities.…”

“…As such, this work directly compares estimated or measured (wherever available) human plasma concentrations with the regenerating planarian LEL media concentrations. Human biomonitoring data were unit-converted using HTTK modeling to estimate internal plasma concentrations in children and consisted of breast milk, handwipes, and house dust, and plasma and cord-blood serum levels of FRs as previously described (Alzualde et al, 2018). Briefly, the 3-compartment model in the HTTK R package (version 1.7) (Pearce et al, 2017;Wambaugh et al, 2015) with input chemical parameters from ADMET Predictor 7.2 (Simulations Plus, Inc., Lancaster, CA, USA) was used.…”

“…While several of the 15 FRs that we screened have been previously studied in other systems, including rodents (Cope et al, 2015;EFSA, 2011;Moser et al, 2015;Nakajima et al, 2009;National Toxicology Program, 1991;Viberg and Eriksson, 2011) and other alternative models (Alzualde et al, 2018;Bailey and Levin, 2015;Cano-Sancho et al, 2017;Glazer et al, 2018;Oliveri et al, 2015;Slotkin et al, 2017;Usenko et al, 2016) with some FRs showing developmental toxicity or DNT. Thus, herein, we compared our planarian data with these published results (Behl et al, 2015;Behl et al, 2016;Jarema et al, 2015;Noyes et al, 2015) to contextualize our findings (Table 3, Figure 4).…”

Screening for neurotoxic potential of 15 flame retardants using freshwater planarians

“…While several of the 15 FRs that we screened have been previously studied in other systems, including rodents (Cope et al, 2015; EFSA, 2011; Moser et al, 2015; Nakajima et al, 2009; National Toxicology Program, 1991; Viberg and Eriksson, 2011) and other alternative models (Alzualde et al, 2018; Bailey and Levin, 2015; Cano-Sancho et al, 2017; Glazer et al, 2018; Oliveri et al, 2015; Slotkin et al, 2017; Usenko et al, 2016), only a handful of studies have performed direct multi-FR comparisons as provided here. Fourteen of the 15 unique FRs tested in this screen have been previously studied in developing zebrafish, nematodes, and in vitro cell-based (mouse embryonic stem cell, human neural stem cell, and rat neuron) systems with some FRs showing developmental toxicity or DNT.…”

“…In addition to comparing with other toxicological models, comparing with human environmental exposure can contextualize the relevancy of observed toxicity in a given system. Therefore, we overlaid our regenerating planarian screening results to measured or estimated in vivo plasma concentrations using the HTTK R-package (Figure 5) (Alzualde et al, 2018; Pearce et al, 2017). The nominal water concentrations at which effects were seen in regenerating planarians are significantly greater (1-2 orders of magnitude) than the highest estimated concentrations based on reported human exposure levels.…”