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. 2023 Feb 17;191(2):374-386.
doi: 10.1093/toxsci/kfac135.

Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats

Shannah K Witchey  1 , Vicki Sutherland  1 , Brad Collins  1 , Georgia Roberts  1 , Keith R Shockley  2 , Molly Vallant  1 , Jeffrey Krause  3 , Helen Cunny  1 , Suramya Waidyanatha  1 , Eve Mylchreest  4 , Barney Sparrow  5 , Robert Moyer  5 , Mamta Behl  1
Affiliations

Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats

Shannah K Witchey et al. Toxicol Sci. .

Abstract

Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in environmental samples around the world. Human exposure primarily occurs via oral ingestion with reported higher concentrations in children. Currently, there are no data to evaluate potential risk from exposure to either TPHP or IPP during fetal development. These short-term perinatal studies in rats provide preliminary toxicity data for TPHP and IPP, including information on transfer to fetus/offspring and across the pup blood-brain barrier. In separate experiments, TPHP or IPP were administered via dosed feed at concentrations 0, 1000, 3000, 10 000, 15 000, or 30 000 ppm to time-mated Hsd:Sprague Dawley SD rats from gestation day (GD) 6 through postnatal day (PND) 28; offspring were provided dosed feed at the same concentration as their dam (PND 28-PND 56). TPHP- and IPP-related toxicity resulted in removal of both 30 000 ppm groups on GD 12 and 15 000 ppm IPP group after parturition. Body weight and organ weights were impacted with exposure in remaining dams. Reproductive performance was perturbed at ≥10 000 ppm TPHP and all IPP exposure groups. In offspring, both TPHP- and IPP-related toxicity was noted in pups at ≥10 000 ppm as well as reduction in bodyweights, delays in pubertal endpoints, and/or reduced cholinesterase enzyme activity starting at 1000 ppm TPHP or IPP. Preliminary internal dose assessment indicated gestational and lactational transfer following exposure to TPHP or IPP. These findings demonstrate that offspring development is sensitive to 1000 ppm TPHP or IPP exposure.

Keywords: developmental neurotoxicity; environmental chemicals; flame retardants; organophosphates; plasticizers.

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Figures

Figure 1.
Figure 1.
Study design summary. Studies examining perinatal exposure to TPHP or IPP followed the same study design outline though conducted separately. Abbreviations: IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 2.
Figure 2.
Mean body weight of (A) TPHP and (B) IPP exposed F0 dams during gestation and lactation. Graphs depict mean ± SEM. Abbreviations: IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 3.
Figure 3.
Mean food consumption of (A) TPHP and (B) IPP exposed F0 dams during gestation and lactation. Graphs depict mean ± SEM. Abbreviations: IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 4.
Figure 4.
Mean body weight (g) of male and female offspring (TPHP [A and B] and IPP [C and D], respectively). Graphs depict mean ± SEM. Abbreviations: IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 5.
Figure 5.
Blood AChE and BChE activity in dams and pups exposed to TPHP (A and B) or IPP (C and D). Each point represents group mean as percent of control (control = 100%) and indicates a dose-dependent decrease in activity. TPHP dams n = 10 (except 15 000 ppm n = 8), male offspring n = 7–8/group and female offspring n = 7–8/group. IPP dams n = 9–10/group, male offspring n = 10 (except 3000 ppm n = 7) and female offspring n = 8–11/group. Abbreviations: AChE, acetylcholinesterase; BChE, butyryl cholinesterase; IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 6.
Figure 6.
Brain AChE and BChE activity in male and female offspring exposed to TPHP (A and B) or IPP (C and D). Each point represents group mean as percent of control (control = 100%) indicating a dose-dependent decrease in activity. TPHP dams n = 10 (except 15000 ppm n = 8), male offspring n = 7–8/group and female offspring n = 7–8/group. IPP dams n = 9–10/group, male offspring n = 10 (except 3000 ppm n = 7) and female offspring n = 8–10/group. Abbreviations: AChE, acetylcholinesterase; BChE, butyryl cholinesterase; IPP, isopropylated phenyl phosphate; TPHP, triphenyl phosphate.
Figure 7.
Figure 7.
Mean concentrations of TPHP (A and B) and IPP components (C and D) during gestation and lactation. Due to toxicity, no samples were collected from dams in 10 000 ppm IPP group on PND 4. TPHP and IPP GD 18 and PND 4 samples n = 3/group. This was a preliminary study and no statistical analysis was performed. Abbreviations: IPP, isopropylated phenyl phosphate; PND, postnatal day; TPHP, triphenyl phosphate.
Figure 8.
Figure 8.
Concentration of TPHP (A) and IPP (B) isomers in plasma and brain of PND 28 offspring. Due to toxicity, no samples were collected for the 10 000 ppm IPP group and only 1000 IPP isomer concentrations reported. In IPP exposed animals, plasma TPHP isomer concentration fell below detection. TPHP samples n = 5–6/group and IPP n = 8–10/group. This was a preliminary study and no statistical analysis was performed. Abbreviations: IPP, isopropylated phenyl phosphate; PND, postnatal day; TPHP, triphenyl phosphate.
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References

    1. Araki A., Bastiaensen M., Ait Bamai Y., Van den Eede N., Kawai T., Tsuboi T., Ketema R. M., Covaci A., Kishi R. (2018). Associations between allergic symptoms and phosphate flame retardants in dust and their urinary metabolites among school children. Environ. Int. 119, 438–446. - PubMed
    1. Bajard L., Melymuk L., Blaha L. (2019). Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from toxcast and adverse outcome pathways. Environ. Sci. Eur. 31, 1–19.
    1. Behl M., Hsieh J. H., Shafer T. J., Mundy W. R., Rice J. R., Boyd W. A., Freedman J. H., Hunter E. S. 3rd, Jarema K. A., Padilla S., et al. (2015). Use of alternative assays to identify and prioritize organophosphorus flame retardants for potential developmental and neurotoxicity. Neurotoxicol. Teratol. 52, 181–193. - PubMed
    1. Behl M., Rice J. R., Smith M. V., Co C. A., Bridge M. F., Hsieh J. H., Freedman J. H., Boyd W. A. (2016). Editor's highlight: Comparative toxicity of organophosphate flame retardants and polybrominated diphenyl ethers to Caenorhabditis elegans. Toxicol. Sci. 154, 241–252. - PMC - PubMed
    1. Blum A., Behl M., Birnbaum L., Diamond M. L., Phillips A., Singla V., Sipes N. S., Stapleton H. M., Venier M. (2019). Organophosphate ester flame retardants: Are they a regrettable substitution for polybrominated diphenyl ethers? Environ. Sci. Technol. Lett. 6, 638–649. - PMC - PubMed

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