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Comparative Toxicity of Organophosphate Flame Retardants and Polybrominated Diphenyl Ethers to Caenorhabditis elegans

Behl M, Rice JR, Smith MV, Co CA, Bridge M, Hsieh JH, Freedman JH, Boyd WA.
Toxicol Sci (2016) DOI: http:/dx.doi.org/10.1093/toxsci/kfw162 PMID: 27566445

Publication

Abstract

With the phasing-out of the polybrominated diphenyl ether (PBDE) flame retardants due to concerns regarding their potential developmental toxicity, the use of replacement compounds such as organophosphate flame retardants (OPFRs) has increased. Limited toxicity data is currently available to estimate the potential adverse health effects of the OPFRs. The toxicological effects of four brominated flame retardants (BFRs), including three PBDEs and 3,3',5,5'-tetrabromobisphenol A, were compared to six aromatic OPFRs and two aliphatic OPFRs. The effects of these chemicals were determined using three biological endpoints in the nematode Caenorhabditis elegans (feeding, larval development and reproduction). Because C. elegans development was previously reported to be sensitive to mitochondrial function, results were compared to those from an in vitro mitochondrial membrane permeabilization (MMP) assay.Overall 11 of the 12 flame retardants were active in one or more C. elegans biological endpoints, with only tris(2-chloroethyl) phosphate inactive across all endpoints including the in vitro MMP assay. For two of the C. elegans endpoints, at least one OPFR had similar toxicity to the PBDEs: triphenyl phosphate (TPHP) inhibited larval development at levels comparable to the three PBDEs; while TPHP and isopropylated phenol phosphate (IPP) affected C. elegans reproduction at levels similar to the PBDE commercial mixture, DE- 71. The PBDEs reduced C. elegans feeding at lower concentrations than any OPFR. In addition, 9 of the 11 chemicals that inhibited C. elegans larval development also caused significant mitochondrial toxicity. These results suggest that some of the replacement aromatic OPFRs may have levels of toxicity comparable to PBDEs.

Figures

Figure 1. Effects of flame retardants on C. elegans larval development and growth.

A, Top left: Groups of 50 L1 nematodes were exposed for 48 h to various concentrations of flame retardants, illustrated by the horizontal bars. Flame retardants are grouped as: aliphatic organophospate flame retardants (OPFRs); aromatic OPFRs; brominated flame retardants including BDEs. The organophosphate pesticide chlorpyifos and aromatic OPFR TOCP were used as positive controls. Lowest effective concentrations (LECs) [dots] and EC50s [crosses] with 95% confidence intervals are also displayed. B, Bottom left: Scatterplots of observed maximum effect size (log(EXT)) and lowest effective concentration (LEC, in log scale). The horizontal dashed line refers to the maximum effect, no growth or development, for this assay. C, Top right: Sample concentration-effect plot for BPDP, a representative OPFR. D, Bottom right: Sample concentration-effect plot for DE-71, a representative PBDE.

Figure 2. Effects of flame retardants on C. elegans feeding.

A, Top left: Groups of 25 adult nematodes were exposed for 24 h to various concentrations of flame retardants, illustrated by the horizontal bars. Flame retardants are grouped as: aliphatic organophospate flame retardants (OPFRs); aromatic OPFRs; brominated flame retardants including BDEs. The organophosphate pesticide chlorpyifos and aromatic OPFR TOCP were used as positive controls. Lowest effective concentrations (LECs) [dots] and EC50s [crosses] with 95% confidence intervals are also displayed. B, Bottom left: Scatterplots of observed maximum effect size (log(EXT)) and lowest effective concentration (LEC, in log scale). The horizontal dashed line refers to the maximum effect, no feeding, for this assay. C, Top right: Sample concentration-effect plot for BPDP, a representative OPFR. D, Bottom right: Sample concentration-effect plot for DE-71, a representative PBDE.

Figure 3. Effects of flame retardants on C. elegans reproduction.

A, Left panel: Groups of 5 L4 nematodes were exposed for 48 h to various concentrations of flame retardants, illustrated by the horizontal bars. Flame retardants are grouped as: aliphatic organophospate flame retardants (OPFRs); aromatic OPFRs; brominated flame retardants including BDEs. The organophosphate pesticide chlorpyifos and aromatic OPFR TOCP were used as positive controls. Lowest effective concentrations (LECs) [dots] and EC50s [crosses] with 95% confidence intervals are also displayed. B, Top right: Sample concentration-effect plot for BPDP, a representative OPFR. C, Bottom right: Sample concentration-effect plot for DE-71, a representative PBDE.

Figure 4. Comparison of flame retardant activity in C. elegans and in vitro MMP assays.

Box and whisker plot displaying the points of departure (PODs) for C. elegans larval development [filled circles], feeding [filled diamonds], and reproduction [filled triangles] as well as qHTS in vitro MMP assay [open circles] and cytotoxicity [open squares]. The x-axis displays chemicals in increasing order of activity from left to right.

Supplemental Materials

Supplementary Data

Associated Publication

Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity.
Behl M, Hsieh JH, Shafer TJ, Mundy WR, Rice JR, Boyd WA, Freedman JH, Hunter ES, Jarema KA, Padilla S, Tice RR.
Neurotoxicol Teratol. (2015), http:/dx.doi.org/10.1016/j.ntt.2015.09.003. PMID: 26386178