A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

Emond, Claude; Raymer, James; Studabaker, William B.; Garner, C. Edwin; Birnbaum, Linda S.

doi:10.1016/j.taap.2009.10.019

Cited by 43 publications

(34 citation statements)

References 49 publications

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“…This type of modelling, of course, is restricted to PBDE exposure at the level of the whole body. In order to allow more refined kinetic modelling for developmental exposure Emond et al (2010) developed a PBPK model for BDE-47 in the rat. Next to an absorption compartment the PBPK model consisted of the following eight compartments: brain, liver, adipose tissue, kidney, placenta, the fetus, the blood and a remaining compartment ("rest of the body").…”

Section: Physiologically Based Pharmacokinetic (Pbpk) Modellingmentioning

confidence: 99%

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

195

147

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EFSA was asked by the European Commission to deliver a scientific opinion on polybrominated diphenyl ethers (PBDEs) in food. PBDEs are additive flame retardants which are applied in plastics, textiles, electronic castings and circuitry. PBDEs are ubiquitously present in the environment and likewise in biota and in food and feed. Data from the analysis of 19 PBDE congeners in 3,971 food samples were provided to EFSA by 11 European countries. Eight congeners were considered by the Panel on Contaminants in the Food Chain (CONTAM Panel) to be of primary interest: . The highest dietary exposure is to . Toxicity studies were carried out with technical PBDE mixtures or individual congeners. Main targets were the liver, thyroid hormone homeostasis and the reproductive and nervous system. PBDEs cause DNA damage through the induction of reactive oxygen species. The Panel identified effects on neurodevelopment as the critical endpoint, and derived benchmark doses (BMDs) and their corresponding lower 95 % confidence limit for a benchmark response of 10 %, BMDL 10 s, for a number of PBDE congeners: BDE-47, 309 μg/kg b.w.; BDE-99, 12 μg/kg b.w.; BDE-153, 83 μg/kg b.w.; BDE-209, 1,700 μg/kg b.w. Due to the limitations and uncertainties in the current database, the Panel concluded that it was inappropriate to use these BMDLs to establish health based guidance values, and instead used a margin of exposure (MOE) approach for the health risk assessment. Since elimination characteristics of PBDE congeners in animals and humans differ considerably, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that for BDE-47, -153 and -209 current dietary exposure in the EU does not raise a health concern. For BDE-99 there is a potential health concern with respect to current dietary exposure. 4 The term "intra-species" has been replaced by "inter-species" in the Summary and in Chapter 9.1. The chemical stability of the PBDE congeners varies with the individual structure. In general PBDE congeners with up to three bromine substituents and those with nine or ten bromine substituents are more sensitive to abiotic transformations. PBDE congeners with four to eight bromine substituents show the highest stability. PBDE congeners are particularly susceptible to photolysis, reductive debromination and radical reactions whereas they are less susceptible to oxidation and hydrolysis. In general, PBDE congeners are persistent and bioaccumulative with the exception of BDE-209 bioaccumulative properties of which seem to be species dependent. BDE-209 undergoes debromination reactions both in the abiotic environment and in biota, leading to formation of PBDE congeners containing seven to nine bromine atoms. © European Food SafetyBased on the composition of the technical PBDE mixtures, occurrence in the environment and in food, the Panel on Contaminants in the Food Chain (CONTAM Panel) considered the following eight PBDE congeners to be of primary interest: which are relevant for dietary PBDE exposur...

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Section: Physiologically Based Pharmacokinetic (Pbpk) Modellingmentioning

confidence: 99%

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

2011

EFS2

195

147

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“…An existing PBPK model developed for the rat did not accurately describe the urinary elimination of BDE-47 in mice (Emond et al 2010). As such, this model was used as the basis for the model applied in the current study, but was modified to evaluate two transporters (i.e., m-MUP and P-gp) in the excretion of BDE-47 in mice.…”

Section: Methodsmentioning

confidence: 99%

“…When comparing the disposition and elimination of BDE-47 in rats and mice, Sanders et al (2006a) noted that internal dose and excretion patterns were different. Emond et al (2010) recently described the kinetic behavior of BDE-47 in rats using a physiologically based pharmacokinetic (PBPK) model. The distribution of BDE-47 is dose dependent in rats and driven by the compound’s high lipophilicity.…”

Section: Introductionmentioning

confidence: 99%

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

Emond

Sanders

Wikoff

et al. 2013

Toxicology and Applied Pharmacology

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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.

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“…Sensitivity analyses can be "local" or "global". During a local sensitivity analysis (LSA), the model predictions are judged against pre-defined changes of for example 1%, 2% or 5% in each separate parameter value and expressed in, for instance, area under the curve (AUC) of the model values [52]. In a global sensitivity analysis (GSA), however, all model parameters vary in pre-defined ranges and their relative influence on the model output is assessed [53].…”

Section: Equationsmentioning

confidence: 99%

Overview of the Current State-of-the-Art for Bioaccumulation Models in Marine Mammals

Weijs

Hickie

Blust

2014

Toxics

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Information regarding the (toxico)kinetics of a chemical in organisms can be integrated in mathematical equations thereby creating bioaccumulation models. Such models can reconstruct previous exposure scenarios, provide a framework for current exposures and predict future situations. As such, they are gaining in popularity for risk assessment purposes. Since marine mammals are protected, the modeling process is different and more difficult to complete than for typical model organisms, such as rodents. This review will therefore discuss the currently available models for marine mammals, address statistical issues and knowledge gaps, highlight future perspectives and provide general do"s and don"ts.

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A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

Cited by 43 publications

References 49 publications

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

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

Overview of the Current State-of-the-Art for Bioaccumulation Models in Marine Mammals

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