Metabolism in the toxicokinetics and fate of brominated flame retardants--a review.

Several classes of brominated flame retardants (BFRs), namely polybrominated biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCCD), bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tris(2,3-dibromopropyl)phosphate (Tris), have been identified as environmental contaminants. PBDEs, TBBPA, and HBCCD are of particular concern due to increasing environmental concentrations and their ubiquitous presence in the tissues of humans and wildlife from Europe, Japan, and North America. Regardless, the toxicokinetics, in particular metabolism, of BFRs has received little attention. The present review summarizes the current state of knowledge of BFR metabolism, which is an important factor in determining the bioaccumulation, fate, toxicokinetics, and potential toxicity of BFRs in exposed organisms. Of the minimal metabolism research done, BFRs have been shown to be susceptible to several metabolic processes including oxidative debromination, reductive debromination, oxidative CYP enzyme-mediated biotransformation, and/or Phase II conjugation (glucuronidation and sulfation).However, substantially more research on metabolism is necessary to fully assess BFR fate, uptake and elimination kinetics, metabolic pathways, inter-species differences, the influence of congener structure, and the potential health risks to exposed organisms.

[1]  D. Fennell,et al.  Anaerobic biotransformation of tetrabromobisphenol A, tetrachlorobisphenol A, and bisphenol A in estuarine sediments. , 2002, Environmental science & technology.

[2]  Sierra Rayne,et al.  Exponential increases of the brominated flame retardants, polybrominated diphenyl ethers, in the Canadian Arctic from 1981 to 2000. , 2002, Environmental science & technology.

[3]  Bo Jansson,et al.  Dietary Uptake and Biological Effects of Decabromodiphenyl Ether in Rainbow Trout (Oncorhynchus mykiss) , 1999 .

[4]  H. Matthews,et al.  Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat. , 1983, Toxicology and applied pharmacology.

[5]  B. Marks,et al.  Tissue distribution and elimination kinetics of polybrominated biphenyls (PBB) from rat tissue. , 1981, Toxicology letters.

[6]  G. Carlson,et al.  Induction of xenobiotic metabolism in rats by brominated diphenyl ethers administered for 90 days. , 1980, Toxicology letters.

[7]  M H Tarbit,et al.  Structural determinants of cytochrome P450 substrate specificity, binding affinity and catalytic rate. , 1998, Chemico-biological interactions.

[8]  J. Szymańska,et al.  The disposition and metabolism of tetrabromobisphenol-A after a single i.p. dose in the rat. , 2001, Chemosphere.

[9]  L. B. Willett,et al.  Distribution and clearance of polybrominated biphenyls in cows and calves. , 1976, Journal of dairy science.

[10]  H. Hakk,et al.  A mass balance feeding study of a commercial octabromodiphenyl ether mixture in rats , 2002 .

[11]  H. Matthews,et al.  Distribution and excretion of 2,2',4,4',5,5'-hexabromobiphenyl in rats and man: pharmacokinetic model predictions. , 1980, Toxicology and applied pharmacology.

[12]  U. Orn,et al.  Metabolism of 2,2',4,4'-tetrabromodiphenyl ether in rat and mouse. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  R. Kimbrough,et al.  Partitioning of polybrominated biphenyls (PBBs) in serum, adipose tissue, breast milk, placenta, cord blood, biliary fluid, and feces. , 1983, Archives of environmental health.

[14]  W. J. Davies,et al.  Frog embryo teratogenesis assay. Xenopus (FETAX). , 1995, Methods in molecular biology.

[15]  B. Vig,et al.  Studies on the antimicrobial substances of sponges. VI. Structures of two antibacterial substances isolated from the marine sponge Dysidea herbacea. , 1972 .

[16]  M. Takatsuki,et al.  Comparison of reporter gene assay and immature rat uterotrophic assay of twenty-three chemicals. , 2002, Toxicology.

[17]  C. A. Wit,et al.  Polybrominated diphenyl ethers (PBDE) in biological samples from the Swedish environment , 1993 .

[18]  Frank A. P. C. Gobas,et al.  Relationship between bioconcentration in fish and steric factors of hydrophobic chemicals , 1985 .

[19]  B. Schwetz,et al.  Toxicology of octabromobiphenyl and decabromodiphenyl oxide. , 1975, Environmental health perspectives.

[20]  L. S. John,et al.  Studies of possible absorption of a flame retardant from treated fabrics worn by rats and humans , 1976, Bulletin of environmental contamination and toxicology.

[21]  U. Bauer,et al.  Metabolic activation of PCBs to quinones: reactivity toward nitrogen and sulfur nucleophiles and influence of superoxide dismutase. , 1996, Chemical research in toxicology.

[22]  K M Crofton,et al.  Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[23]  L. Johnson,et al.  Structure of human transthyretin complexed with bromophenols: a new mode of binding. , 2000, Acta crystallographica. Section D, Biological crystallography.

[24]  C. D. de Wit An overview of brominated flame retardants in the environment. , 2002, Chemosphere.

[25]  P. B. Larsen,et al.  Polybrominated diphenyl ethers: occurrence, dietary exposure, and toxicology. , 2001, Environmental health perspectives.

[26]  R N Stillwell,et al.  Children absorb tris-BP flame retardant from sleepwear: urine contains the mutagenic metabolite, 2,3-dibromopropanol. , 1978, Science.

[27]  J. Borlakoglu,et al.  Microsomal oxidation of bromo-, chloro- and fluorobiphenyls. , 1993, Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology.

[28]  C. A. Wit An overview of brominated flame retardants in the environment. , 2002 .

[29]  B. Jansson,et al.  Analysis of tetrabromobisphenol A in a product and environmental samples , 1995 .

[30]  O. Hutzinger,et al.  Uptake of chloro- and bromobiphenyls, hexachloro- and hexabromobenzene by fish , 1976, Bulletin of environmental contamination and toxicology.

[31]  Lillemor Asplund,et al.  Organohalogen substances in muscle, egg and blood from healthy Baltic salmon (Salmo salar) and Baltic salmon that produced offspring with the M74 syndrome , 1999 .

[32]  S. Aust,et al.  Studies on the microsomal metabolism and binding of polybrominated biphenyls (PBBs). , 1978, Environmental health perspectives.

[33]  F. Guengerich,et al.  Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes. , 1985, Toxicology and applied pharmacology.

[34]  I. Meerts,et al.  Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[35]  A Schmoldt,et al.  Induction of rat liver microsomal cytochrome P-450 by the pentabromo diphenyl ether Bromkal 70 and half-lives of its components in the adipose tissue. , 1990, Toxicology.

[36]  R. Letcher,et al.  Methyl Sulfone and Hydroxylated Metabolites of Polychlorinated Biphenyls , 2000 .

[37]  C. A. Wit,et al.  Effects of two polybrominated diphenyl ethers on rainbow trout (Oncorhynchus mykiss) exposed via food , 1998 .

[38]  J. Boer,et al.  Polybrominated Biphenyls and Diphenylethers , 2000 .

[39]  H. Matthews,et al.  In vivo binding of the flame retardantsTris(2,3-dibromopropyl) phosphate andTris(1,3-dichloro-2-propyl) phosphate to macromolecules of mouse liver, kidney and muscle , 1980, Bulletin of environmental contamination and toxicology.

[40]  P Krahn,et al.  Book Review: Environmental Health Criteria 190. International Programme on Chemical Safety (IPCS). , 1997, Annals of Saudi medicine.

[41]  N. Olson,et al.  Analysis and Occurrence of Polybrominated Diphenyl Ethers in Washington State Freshwater Fish , 2001, Archives of environmental contamination and toxicology.

[42]  N. Gerber,et al.  Diester metabolites of the flame retardant chemicals, tris(1,3-dichloro-2-propyl)phosphate and tris(2,3-dibromopropyl) phosphate in the rat: identification and quantification. , 1980, Research communications in chemical pathology and pharmacology.

[43]  W. Dauterman Biological and nonbiological modifications of organophosphorus compounds. , 1971, Bulletin of the World Health Organization.

[44]  V. Hertzberg,et al.  Determinants of polybrominated biphenyl serum decay among women in the Michigan PBB cohort. , 2000, Environmental health perspectives.

[45]  A. Bergman,et al.  Nestling blood of the white-tailed sea eagle (Haliaeetus albicilla) as an indicator of territorial exposure to organohalogen compounds: An evaluation , 2000 .

[46]  J. Boer,et al.  Do flame retardants threaten ocean life? , 1998, Nature.

[47]  Aharon Abeliovich,et al.  Anaerobic-Aerobic Process for Microbial Degradation of Tetrabromobisphenol A , 2000, Applied and Environmental Microbiology.

[48]  Thomas A McDonald,et al.  A perspective on the potential health risks of PBDEs. , 2002, Chemosphere.

[49]  Eva Jakobsson,et al.  Gas chromatographic identification and quantification of polybrominated diphenyl ethers in a commercial product, Bromkal 70-5DE , 1998 .

[50]  W. Stremmel,et al.  Uptake of fatty acids by jejunal mucosal cells is mediated by a fatty acid binding membrane protein. , 1988, The Journal of clinical investigation.

[51]  J. Kennish,et al.  Metabolism, distribution, and excretion of the flame retardant, tris(2,3-dibromopropyl) phosphate (tris-bp) in the rat: identification of mutagenic and nephrotoxic metabolites. , 1982, Toxicology and applied pharmacology.

[52]  S. Safe,et al.  FireMaster BP-6: fractionation, metabolic and enzyme induction studies. , 1978, Environmental health perspectives.

[53]  O. Hutzinger,et al.  Metabolism of 4,4'-dihalogenobiphenyls. , 1976, Journal of the Chemical Society. Perkin transactions 1.

[54]  Polybrominated biphenyls. , 1978, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

[55]  E. Ghisalberti,et al.  Structural studies of halogenated diphenyl ethers from a marine sponge , 1981 .

[56]  R. Renner What fate for brominated fire retardants? , 2000, Environmental science & technology.

[57]  M. Wolff,et al.  PBB homologs in sera of Michigan dairy farmers and Michigan chemical workers. , 1978, Environmental health perspectives.

[58]  S. Safe,et al.  Metabolism of bromobiphenyls. , 1978, Biochemical pharmacology.

[59]  Nathan G Dodder,et al.  Concentrations and spatial variations of polybrominated diphenyl ethers and several organochlorine compounds in fishes from the northeastern United States. , 2002, Environmental science & technology.

[60]  J. H. Christensen,et al.  Screening of polybrominated diphenyl ethers in blue mussels, marine and freshwater sediments in Denmark. , 2001, Journal of environmental monitoring : JEM.

[61]  M. Gilek,et al.  Bioaccumulation kinetics of brominated flame retardants (polybrominated diphenyl ethers) in blue mussels (Mytilus edulis) , 1999 .

[62]  G. Larsen,et al.  Tissue disposition, excretion and metabolism of 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99) in the male Sprague-Dawley rat , 2002, Xenobiotica; the fate of foreign compounds in biological systems.

[63]  T. Andersson,et al.  Species-specific accumulation of the polychlorinated biphenyl (PCB) 2,3,3',4,4'-pentachlorobiphenyl in fish brain: a comparison between cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). , 1990, Pharmacology & toxicology.

[64]  R. Norstrom,et al.  Geographical distribution (2000) and temporal trends (1981-2000) of brominated diphenyl ethers in Great Lakes hewing gull eggs. , 2002, Environmental science & technology.

[65]  K. Tollefsen Interaction of estrogen mimics, singly and in combination, with plasma sex steroid-binding proteins in rainbow trout (Oncorhynchus mykiss). , 2002, Aquatic toxicology.

[66]  L. Hagmar,et al.  Biological half-lives of polybrominated diphenyl ethers and tetrabromobisphenol a in exposed workers , 2000 .

[67]  B. Brunström,et al.  Effects of bisphenol A and tetrabromobisphenol A on sex organ development in quail and chicken embryos , 2001, Environmental toxicology and chemistry.

[68]  W. Flanders,et al.  Half-life of polybrominated biphenyl in human sera. , 1995, Environmental health perspectives.

[69]  H. Matthews,et al.  Distribution and excretion of 2,4,5,2',4',5'-hexabromobiphenyl, the major component of Firemaster BP-6. , 1977, Journal of toxicology and environmental health.

[70]  P. Burkholder,et al.  Studies on the antimicrobial substances of sponges. II. Structure and synthesis of a bromine-containing antibacterial compound from a marine sponge. , 1967, Tetrahedron letters.

[71]  A. Pijnenburg,et al.  Polybrominated biphenyl and diphenylether flame retardants: analysis, toxicity, and environmental occurrence. , 1995, Reviews of environmental contamination and toxicology.

[72]  L. Norrgren,et al.  Influences of halogenated organic substances on ovarian development and hepatic EROD activity in the three-spined stickleback, Gasterosteus aculeatus, and rainbow trout, Oncorhynchus mykiss , 1994 .

[73]  G. Larsen,et al.  Metabolism, excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[74]  S. Cagen,et al.  Distribution of polybrominated biphenyls after dietary exposure in pregnant and lactating rats and their offspring. , 1978, Environmental health perspectives.

[75]  D W Nebert,et al.  P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. , 1996, Pharmacogenetics.

[76]  M. Oehme,et al.  Interspecies differences in tissue distribution of 2,3,7,8-tetrachlorodibenzo-p-dioxin between cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss) , 1992 .

[77]  R. Tatsukawa,et al.  Identification of the flame retardant tetrabromobisphenol-a in the river sediment and the mussel collected in Osaka , 1983, Bulletin of environmental contamination and toxicology.

[78]  G. Fries,et al.  Excretion of polybrominated biphenyls into the milk of cows. , 1975, Journal of dairy science.

[79]  S. Safe,et al.  The metabolism of brominated aromatic compounds , 1976 .

[80]  Tommy Andersson,et al.  Liver morphology and cytochrome P450 activity in fry of rainbow trout after microinjection of lipid-soluble xenobiotics in the yolk-sac embryos , 1993 .

[81]  K. Drouillard,et al.  Plasma-associated halogenated phenolic contaminants in benthic and pelagic fish species from the Detroit River. , 2003, Environmental Science and Technology.

[82]  G. Koss,et al.  2,2',4,4',5,5'-hexabromobiphenyl: its toxicokinetics, biotransformation and porphyrinogenic action in rats. , 1994, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[83]  G. Carlson,et al.  Induction of xenobiotic metabolism in rats by short-term administration of brominated diphenyl ethers. , 1980, Toxicology letters.

[84]  T. Kawamura,et al.  The mutagenicity of halogenated alkanols and their phosphoric acid esters for Salmonella typhimurium. , 1979, Mutation research.

[85]  N. Bunce,et al.  Synthesis of polybrominated diphenyl ethers and their capacity to induce CYP1A by the Ah receptor mediated pathway. , 2001, Environmental science & technology.

[86]  W. K. Porter,et al.  Percutaneous absorption of radiolabeled TRIS from flame-retarded fabric. , 1978, Journal of environmental pathology and toxicology.

[87]  R C Hale,et al.  Polybrominated diphenyl ether flame retardants in Virginia freshwater fishes (USA). , 2001, Environmental science & technology.

[88]  V. Zitko The accumulation of polybrominated biphenyls by fish , 1977, Bulletin of environmental contamination and toxicology.

[89]  A. Nomeir,et al.  Disposition of the flame retardant 1,2-bis(2,4,6-tribromophenoxy)ethane in rats following administration in the diet. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[90]  U Orn,et al.  Tissue distribution of 2,2',4,4'-tetrabromo[14C]diphenyl ether ([14C]-PBDE 47) in pike (Esox lucius) after dietary exposure--a time series study using whole body autoradiography. , 2000, Chemosphere.

[91]  A. Arukwe,et al.  The expression of CYP1A, vitellogenin and zona radiata proteins in Atlantic salmon (Salmo salar) after oral dosing with two commercial PBDE flame retardant mixtures: absence of short-term responses. , 2002, Marine environmental research.

[92]  R Devoret,et al.  Bacterial tests for potential carcinogens. , 1979, Scientific American.

[93]  R. Tatsukawa,et al.  Formation of brominated dibenzofurans from the photolysis of flame retardant decabromobiphenyl ether in hexane solution by UV and sun light , 1987, Bulletin of environmental contamination and toxicology.

[94]  L. Hovander,et al.  Identification of Hydroxylated PCB Metabolites and Other Phenolic Halogenated Pollutants in Human Blood Plasma , 2002, Archives of environmental contamination and toxicology.

[95]  K. Solomon,et al.  Spatial and temporal distribution of polybrominated diphenyl ethers in lake trout from the Great Lakes , 2000 .

[96]  P. Grover,et al.  Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. , 1974, Advances in cancer research.

[97]  R. Letcher,et al.  Halogenated phenolic contaminants and metabolites in the blood of killer whale (Orcinus orca) , 2002 .

[98]  D. Schoeller,et al.  The caffeine breath test and caffeine urinary metabolite ratios in the Michigan cohort exposed to polybrominated biphenyls: a preliminary study. , 1990, Environmental health perspectives.

[99]  K. Norén,et al.  Certain organochlorine and organobromine contaminants in Swedish human milk in perspective of past 20-30 years. , 2000, Chemosphere.

[100]  S. E. el Dareer,et al.  Disposition of decabromobiphenyl ether in rats dosed intravenously or by feeding. , 1987, Journal of toxicology and environmental health.

[101]  H. Wilkes,et al.  Biodegradation of diphenyl ether and its monohalogenated derivatives by Sphingomonas sp. strain SS3 , 1992, Applied and environmental microbiology.

[102]  L. B. Willett,et al.  Effects of PBBs on cattle. IV. Distribution and clearance of components of firemaster BP-6. , 1978, Environmental health perspectives.

[103]  Dag Broman,et al.  Dietary uptake in pike (Esox lucius) of some polychlorinated biphenyls, polychlorinated naphthalenes and polybrominated diphenyl ethers administered in natural diet , 1997 .

[104]  A. Bergman,et al.  Flame retardants in indoor air at an electronics recycling plant and at other work environments. , 2001, Environmental science & technology.

[105]  F. Korte,et al.  Microbial decomposition of sodium pentachlorophenolate , 1979 .

[106]  D. Faulkner,et al.  Polybrominated Diphenyl Ethers from Dysidea herbacea, Dysidea chlorea and Phyllospongia foliascens , 1981 .

[107]  T. Visser,et al.  Interactions of Persistent Environmental Organohalogens With the Thyroid Hormone System: Mechanisms and Possible Consequences for Animal and Human Health , 1998, Toxicology and industrial health.

[108]  A. Hanberg,et al.  Swedish dioxin survey: evaluation of the H-4-II E bioassay for screening environmental samples for dioxin-like enzyme induction. , 1991, Pharmacology & toxicology.

[109]  Peter Haglund,et al.  Identification and Quantification of Polybrominated Diphenyl Ethers and Methoxy-Polybrominated Diphenyl Ethers in Baltic Biota , 1997 .