Abstract
Introduction
Flame retardants have wide industrial applications and are incorporated into articles found in automobiles and home environments, including seat cushions. These compounds differ widely chemically and in their toxic potential. We report here two cases involving dogs following ingestion of car seat cushions impregnated with organophosphate ester fire retardants.
Case Reports
Two case reports are presented. Two adult American Pit Bull dogs were presented at an emergency clinic with acute signs of central nervous system excitation including seizures. The most severely affected dog died 15 min after presentation, while the less affected dog fully recovered following treatment. In the second case, both a German Shepherd and a Rottweiler were found dead in the morning after they were left in a car overnight. A comprehensive toxicological analysis of samples from both cases revealed the presence of significant amounts (>2 ppm) of tris(2-chloroethyl)phosphate (TCEP) in stomach contents. This compound is a known inducer of epileptic seizures. Some other structurally related organophosphate ester compounds were found, and their role in the acute intoxications reported here is not known and remains to be determined.
Conclusion
This is the first report linking acute deaths in dogs to the ingestion of car seat cushions found to contain large amounts of TCEP, an organophosphate ester compound. It is highly likely that this compound caused death through its known seizure-inducing activity.
Keywords: Organophosphorus flame retardants, Seizures, Tris(2-chloroethyl) phosphate (TCEP), Tris(1-chloro-2-propyl) phosphate (TCPP), Dogs
Full Text
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Acknowledgements
The authors would like to thank Dr. Ray Hostetter, DVM, and Dr. Russel Seifferlein, DVM, for the information and the data provided on case reports no. 1 and 2, respectively.
References
- 1.Environmental Health Criteria no. 192. Flame retardants: a general introduction. Geneva: World Health Organization; 1997. [Google Scholar]
- 2.Reemtsma T, Quintana JB, Rodil R, García-López M, Rodríguez I.Organophosphorus flame retardants and plasticizers in water and air. I. Occurrence and fate Trends Analyt Chem 200827727–737.10.1016/j.trac.2008.07.002 [Google Scholar]
- 3.Hardy ML. The toxicology of the three commercial polybrominated diphenyl oxide (ether) flame retardants. Chemosphere. 2002;46:757–777. doi: 10.1016/s0045-6535(01)00240-5. [DOI] [PubMed] [Google Scholar]
- 4.Mikula P, Svóbodova Z.Brominated flame retardants in the environment: their sources and effects (a review) Acta Vet Brno 200675587–599.10.2754/avb200675040587 [Google Scholar]
- 5.Darnerud PO, Eriksen GS, Jóhannesson T, Larsen PB, Viluksela M. Polybrominated diphenyl ethers: occurrence, dietary exposure, and toxicology. Environ Health Perspect. 2001;109(Suppl 1):49–68. doi: 10.1289/ehp.01109s149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Darnerud PO. Toxic effects of brominated flame retardants in man and in wildlife. Environ Int. 2003;29:841–853. doi: 10.1016/S0160-4120(03)00107-7. [DOI] [PubMed] [Google Scholar]
- 7.Marklund A, Andersson B, Haglund P. Screening of organophosphorus compounds and their distribution in various indoor environments. Chemosphere. 2003;53:1137–1146. doi: 10.1016/S0045-6535(03)00666-0. [DOI] [PubMed] [Google Scholar]
- 8.García-López M, Rodrígueza I, Celaa R, Kroening KK, Caruso JA. Determination of organophosphate flame retardants and plasticizers in sediment samples using microwave-assisted extraction and gas chromatography with inductively coupled plasma mass spectrometry. Talanta. 2009;79:824–829. doi: 10.1016/j.talanta.2009.05.006. [DOI] [PubMed] [Google Scholar]
- 9.Sakamoto T, Sawada Y, Nishide K, Sadamitsu D, Yoshioka T, Sugimoto T, Nishii S, Kishi H. Delayed neurotoxicity produced by an organophosphorous compound (Sumithion) Arch Toxicol. 1984;56:136–138. doi: 10.1007/BF00349087. [DOI] [PubMed] [Google Scholar]
- 10.Valvassori SS, Fortunato JJ, Gomes KM, Reus GZ, Martins MR, Gavioli EC, Schetinger MRC, Dal-Pizzol F, Quevedo J. Acute and subacute exposure to malathion impairs aversive but not non-associative memory in rats. Neurotox Res. 2007;12:71–80. doi: 10.1007/BF03033902. [DOI] [PubMed] [Google Scholar]
- 11.Schmidt G, Gruetzmacher J.Late effects on respiration and circulation following successful treatment of Para-oxon (organophosphate) poisoning with cholinesterase reactivators and atropine in cats Archiv fuer Toxikologie 196924102–122.10.1007/BF00577818 [PubMed] [Google Scholar]
- 12.Lee J-C, Lin K-L, Lin J-J, Hsia S-H, Wu C-T. Non-accidental chlorpyrifos poisoning—an unusual cause of profound unconsciousness. Eur J Pediatr. 2010;169:509–511. doi: 10.1007/s00431-009-1054-5. [DOI] [PubMed] [Google Scholar]
- 13.Sheftel VO. Indirect food additives and polymers. Migration and toxicology. Boca Raton: Lewis; 2000. p. 220. [Google Scholar]
- 14.Lefaux R. Practical toxicology of plastics. Cleveland: CRC; 1968. p. 336. [Google Scholar]
- 15.Laham S, Long G, Schrader K, Szabo J. Induction of electrophysiological and morphological changes in Sprague–Dawley rats fed tributoxyethyl phosphate. J Appl Toxicol. 1984;4:42–48. doi: 10.1002/jat.2550040109. [DOI] [PubMed] [Google Scholar]
- 16.Saitoh M, Umemura T, Kawasaki Y, Momma J, Matusuhima Y, Matusumoto M, et al. Subchronic toxicity study of tributoxyethyl phosphate in Wistar rats. Bull Natl Inst Hyg Sci. 1994;112:27–39. [PubMed] [Google Scholar]
- 17.Carrington CD, Lapadula DM, Othman M, Farr C, Nair RS, Johannse F, et al. Assessment of the delayed neurotoxicity of tributyl phosphate, tributoxyethyl phosphate and dibutylphenyl phosphate. Int J Occup Med Tox. 1996;5:61–68. doi: 10.1177/074823379000600305. [DOI] [PubMed] [Google Scholar]
- 18.Sato T, Watanabe K, Nagase H, Kito H, Niikawa M, Yoshioka Y.Investigation of the hemolytic effects of various organophosphoric acid triesters (OPEs) and their structure–activity relationship Toxicol Environ Chem 199759305–313.10.1080/02772249709358444 [Google Scholar]
- 19.Laham S, Broxup BR, Long GW. Subchronic oral toxicity of tributoxyethyl phosphate in the Sprague–Dawley rat. Arch Environ Health. 1985;40:12–17. doi: 10.1080/00039896.1985.10545882. [DOI] [PubMed] [Google Scholar]
- 20.Ingerowski G, Firedle A, Thumulla J. Chlorinated ethyl and isopropyl phosphoric acid triesters in the indoor environment—an interlaboratory exposure study. Indoor Air. 2001;11:145–149. doi: 10.1034/j.1600-0668.2001.011003145.x. [DOI] [PubMed] [Google Scholar]
- 21.Hartmann PC, Bürgi D, Giger W. Organophosphate flame retardants and plasticizers in indoor air. Chemospher. 2004;57:781–787. doi: 10.1016/j.chemosphere.2004.08.051. [DOI] [PubMed] [Google Scholar]
- 22.Tilson HA, Veronesi B, McLamb RL, Matthews HB. Acute exposure to tris(2-chloroethyl)phosphate produces hippocampal neuronal loss and impairs learning in rats. Toxicol Appl Pharmacol. 1990;106:254–269. doi: 10.1016/0041-008x(90)90245-p. [DOI] [PubMed] [Google Scholar]
- 23.Umezu T, Yonemoto J, Soma Y, Susuki T. Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism. Toxicol Appl Pharmacol. 1998;148:109–116. doi: 10.1006/taap.1997.8312. [DOI] [PubMed] [Google Scholar]
- 24.Environmental Health Criteria no. 209. Flame retardants: tris(chloropropyl) phosphate and tris(2-chloroethyl) phosphate. Geneva: World Health Organization; 1998. [Google Scholar]
- 25.Hughes MF, Edwards BC, Mitchell CT, Bhooshan B. In vitro dermal absorption of flame retardant chemicals. Food Chem Toxicol. 2001;39:1263–1270. doi: 10.1016/s0278-6915(01)00074-6. [DOI] [PubMed] [Google Scholar]
- 26.Gregory NG, Constantine E. Hyperthermia in dogs left in cars. Vet Rec. 1996;139:349–350. doi: 10.1136/vr.139.14.349-b. [DOI] [PubMed] [Google Scholar]
- 27.Rieders F. Cyanides: type B procedure. In: Sunshine I, editor. Methodology for analytical toxicology. West Palm Beach: CRC; 1975. pp. 120–122. [Google Scholar]
- 28.Reynolds JD. Extraction and identification of ten anticoagulant rodenticides from baits and stomach contents by high pressure liquid chromatography. Proc Annu Meet Am Assoc Vet Lab Diag. 1980;23:187–194. [Google Scholar]
- 29.Anderson JJ, Byrd WM, Jr., Camacho VG (1970) Phosphorothioates and their use in flame-retardant polymeric material. Ger. Offen. 59pp. Patent # DE 2024392 19701126. Patent written in German
- 30.Mikhailov M, Stoeva S. Preparation of tris(beta, beta', beta"-chloroethyl)phosphite and its use as a plasticizer and stabilizer of poly(vinyl chloride) Godishnik Visshiya Khimiko Tekhnologichen Inst Burgas. 1978;12:133–140. [Google Scholar]
- 31.Sanchez-Hernandez, Walker CH.In vitro and in vivo cholinesterase inhibition in lacertides by phosphonate- and phosphorothioate-type organophosphates Pesticide Biochem Physiol 2000671–12.10.1006/pest.1999.2471 [Google Scholar]
- 32.Amitai G, Moorad D, Adani R, Doctor BP. Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon. Biochem Pharmacol. 1998;56:293–299. doi: 10.1016/s0006-2952(98)00035-5. [DOI] [PubMed] [Google Scholar]
- 33.Burka LT, Sanders JM, Herr DW, Mathews HB. Metabolism of tris(2-chloroethyl)phosphate in rat and mice. Drug Metab Dispos. 1991;19:443–447. [PubMed] [Google Scholar]
- 34.Eldefrawi AT, Mansour NA, Brattsten LB, Ahrens VD, Lisk DJ. Further toxicological studies with commercial and candidate flame retardant chemicals. Part II Bull Environ Contam Toxicol. 1977;17:720–726. doi: 10.1007/BF01685960. [DOI] [PubMed] [Google Scholar]
- 35.Matthews HB, Dixon D, Herr DW, Tilson H. Subchronic toxicity studies indicate that tris(2-chloroethyl) phosphate administration results in lesions in the rat hippocampus. Toxicol Ind Health. 1990;1:1–15. doi: 10.1177/074823379000600101. [DOI] [PubMed] [Google Scholar]
- 36.Sprague GL, Sandvik LL, Brookins-Hendricks MJ, Bickford AA. Neurotoxicity of two organophosphorus ester flame retardants in hens. J Toxicol Environ Health. 1981;8:507–518. doi: 10.1080/15287398109530087. [DOI] [PubMed] [Google Scholar]
- 37.Ben-Ari Y. Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci. 2002;3:728–739. doi: 10.1038/nrn920. [DOI] [PubMed] [Google Scholar]
- 38.Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–564. doi: 10.1038/nrn1430. [DOI] [PubMed] [Google Scholar]
- 39.Minegishi K, Kurebayashi H, Nambaru S, Morimoto K, Takahashi T, Yamaha T. Comparative studies on absorption, distribution, and excretion of halogenated alkyl phosphate flame retardants in rats. Eisei Kagaku. 1988;34:102–114. [Google Scholar]
- 40.Föllmann W, Wober J. Investigation of cytotoxic, genotoxic, mutagenic, and estrogenic effects of the flame retardants tris-(2-chloroethyl)-phosphate (TCEP) and tris-(2-chloropropyl)-phosphate (TCPP) in vitro. Toxicol Lett. 2006;161:124–134. doi: 10.1016/j.toxlet.2005.08.008. [DOI] [PubMed] [Google Scholar]
- 41.United Nations Environment Programme (2005 ) International Programme on Chemical Safety Monograph [webpage on the Internet]. Tris(1-chloro-2-propyl)phosphate CAS No. 13674-84-5. United Nations Environment Programme, Geneva. http://www.inchem.org/documents/sids/sids/13674845.pdf
- 42.Himmelsbach M, Buchberger W, Reingruber E.Determination of polymer additives by liquid chromatography coupled with mass spectrometry. A comparison of atmospheric pressure photoionization (APPI), atmospheric pressure chemical ionization (APCI), and electrospray ionization (ESI) Polym Degrad Stab 2009941213–1219.10.1016/j.polymdegradstab.2009.04.021 [Google Scholar]
- 43.Stimberg HJ, Galinke J, Gruenberger E (1970) Polyurethane foam. (Henkel und Cie. G.m.b.H.). Ger. Offen. 11 pp. Patent # DE 1800460. Patent written in German
- 44.Anonymous (1971) Self-extinguishable rigid foams based on polyurethanes and addition compounds of urea and formaldehyde. (Crediplast). Fr. 14 pp. Patent # FR 2051948 Patent written in French
- 45.Iordanskaya OA, Shoshtaeva MV, Turetskii LV, Kalinin BA (1979) Rigid polyurethane foam compositions. (USSR). U.S.S.R. Patent # SU 642327 19790115 Patent written in Russian
- 46.Anonymous (1979) Improvements in or relating to the production of polyurethane foam. (Tenneco Chemicals, Inc., USA). Brit. 11 pp. Patent # GB 1546705 19790531 Patent written in English
- 47.Kennedy RB. Polyurethane foams. (USA) (1983) PCT Int. Appl. 29 pp. Patent # WO 8302120. Patent written in English
- 48.Yasui S, Nagata K (1985) Polyurethane foams. (Sanyo Chemical Industries Ltd., Japan). Jpn. Kokai Tokkyo Koho. 8 pp. Patent # JP 60133020. Patent written in Japanese
- 49.Buchanan MS, Davis GB, Greenhouse WVV (1989) Polyurethane foams containing organofunctional silanes. (William T. Burnett and Co., Inc., USA). U.S. 7 pp. Patent # US 4839393. Patent written in English
- 50.Wurpel JN, Hirt PC, Bidanset JH. Amygdala kindling in immature rats: proconvulsant effect of the organophosphate insecticide-chlorpyrifos. Neurotoxicology. 1993;14:429–436. [PubMed] [Google Scholar]
- 51.Karanth S, Pope C. In vitro inhibition of blood cholinesterase activities from horse, cow, and rat by tetrachlorvinphos. Int J Toxicol. 2003;22:429–433. doi: 10.1177/109158180302200604. [DOI] [PubMed] [Google Scholar]
- 52.Gromysz-Kałkowska K, Szubartowska EL. Toxicity of tetrachlorvinphos to Rana temporaria L. Comp Biochem Physiol C. 1993;105:285–290. doi: 10.1016/0742-8413(93)90209-4. [DOI] [PubMed] [Google Scholar]