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

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.

Global marine pollutants inhibit P-glycoprotein: Environmental levels, inhibitory effects, and cocrystal structure

“…For instance, at sites of excretion, metabolism pathways, including those involved in conjugation and oxidation, might mitigate some of the inhibitory effects of pollutants and alter their potential for transport. Indeed, in mice, PBDE-47 is conjugated to carrier proteins that improve its efflux by P-gp into urine ( 62 ). In addition, other ABC transporters, such as ABCC1, ABCC2, and ABCG2, show a broad tissue distribution and can serve as an additional line of defense by expelling modified and/or unmodified pollutants ( 16 , 24 , 40 , 63 , 64 ).…”

PBDE-47 and PBDE mixture (DE-71) toxicities and liver transcriptomic changes at PND 22 after in utero/postnatal exposure in the rat

“…The neonate is particularly vulnerable to toxic chemicals in the environment (Landrigan and Goldman 2011). The pups had higher PBDE congener tissue levels than the dam which was attributed to undeveloped metabolic and excretion capabilities (Coughtrie et al 1988; Emond et al 2013). Toxic endpoints included liver transcript changes and decreases in thyroid hormone levels, and these treatment-related changes were similar after exposure to either the PBDE-47 congener or the PBDE mixture.…”

Mathematical modeling and simulation in animal health – Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

“…Elimination of veterinary drugs and their metabolites, similar to environmental chemicals, is mainly through urinary and biliary pathways. Urinary and biliary excretion can be described using a first-order linear equation or a saturable nonlinear transport model (Clewell et al, 2008;Emond et al, 2013).…”