Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

Toxicol Appl Pharmacol. 2013 Dec 1;273(2):335-44. doi: 10.1016/j.taap.2013.09.007. Epub 2013 Sep 19.

Abstract

Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes.

Keywords: 2,2′,4,4′-tetrabromodiphenyl ether; ABC; ANOVA; ATP; BDE-47; FVB-KO; FVB-WT; Friend virus B-type Mdr1a/b(+/+) wild-type (mice); Friend virus B-type Mdr1a/b(−/−)-deficient knockout (mice); GIT; MRP; Mdr; Mouse; NIH; National Institutes of Health; OAT; OCT; ODS; P-glycoprotein; P-gp; PBDE; PBPK; PND; Postnatal Day; R(t); SA; SD; T3; T4; adenosine triphosphate; adenosine triphosphate-binding cassette; analysis of variance; gastrointestinal tract; m-MUP; mouse major urinary protein; multi-drug resistance; multi-drug resistance-associated protein; octadecylsilane; organic anion transporter; organic cation transporter; physiologically based pharmacokinetic; polybrominated diphenyl ethers; retention time; sensitivity analysis; standard deviation; thyroxine; triiodothyronine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • Animals
  • Dose-Response Relationship, Drug
  • Halogenated Diphenyl Ethers / pharmacokinetics*
  • Halogenated Diphenyl Ethers / urine*
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Biological*
  • Multidrug Resistance-Associated Proteins / deficiency
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / physiology
  • Rats
  • Tissue Distribution / drug effects
  • Tissue Distribution / genetics

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Halogenated Diphenyl Ethers
  • Multidrug Resistance-Associated Proteins
  • 2,2',4,4'-tetrabromodiphenyl ether
  • multidrug resistance-associated protein 2
  • multidrug resistance-associated protein 1