Publications by authors named "Nele Van den Eede"

32 Publications

Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

Eur J Drug Metab Pharmacokinet 2021 Jul 23. Epub 2021 Jul 23.

Department of Pharmacy, Univesity Hospitals Leuven, Leuven, Belgium.

Background: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable.

Objective: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV.

Methods: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling.

Results: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained.

Conclusion: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance.

Trial Registration: ClinicalTrials.gov ID: NCT02365272.
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http://dx.doi.org/10.1007/s13318-021-00698-wDOI Listing
July 2021

Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.

Environ Res 2020 04 3;183:109212. Epub 2020 Feb 3.

Hokkaido University, Center for Environmental and Health Sciences, Kita 12, Nishi 7, Kita-ku, Sapporo, 060-0812, Japan. Electronic address:

Background: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures.

Objectives: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children.

Methods: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income.

Results: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group.

Conclusions: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.
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http://dx.doi.org/10.1016/j.envres.2020.109212DOI Listing
April 2020

Towards establishing indicative values for metabolites of organophosphate ester contaminants in human urine.

Chemosphere 2019 Dec 12;236:124348. Epub 2019 Jul 12.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium. Electronic address:

In 2015, nine laboratories from Belgium, USA, Canada, China, and Australia participated in an interlaboratory exercise to quantify metabolites of organophosphate ester (OPE) contaminants in pooled human urine. Pooled human urine available as SRM 3673 (Organic contaminants in non-smokers' urine) was obtained from the U.S. National Institute of Standards and Technology and was analyzed for its content of OPE metabolites. Each participating laboratory received 10 mL sample and used its own validated method and standards to report the concentrations of the OPE metabolites of its choice. Four OPE metabolites were consistently measured by most laboratories and they were the following diesters: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), bis(2-chloroethyl) phosphate (BCEP), and bis(1-chloro-2-propyl) phosphate (BCIPP). Concentrations of other OPE metabolites in SRM 3673 were also reported but are only considered as informative values since they were measured by three laboratories at most. All laboratories used liquid chromatography with tandem mass spectrometry (LC-MS/MS) with or without solid-phase extraction (SPE). This is the first study to report indicative values for OPE metabolites in a human urine Standard Reference Material. It is expected that these indicative values obtained for these four metabolites will be used as quality control to ensure compatibility of results in biomonitoring studies and by other researchers who validate their own methods for the quantification of OPE metabolites in human urine.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124348DOI Listing
December 2019

Biomonitoring of organophosphate flame retardants and plasticizers in children: Associations with house dust and housing characteristics in Japan.

Environ Res 2019 05 1;172:543-551. Epub 2019 Mar 1.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium. Electronic address:

Indoor environments contain a wide range of new chemicals such as phosphate flame retardants and plasticizers (PFRs). Despite recent epidemiological evidence suggesting that children might be affected by widespread exposure to PFRs, questions remain about the various exposure pathways to these chemicals. Therefore, the aim of this study was to investigate exposure to PFRs by measuring the concentrations a set of urinary metabolites for schoolchildren from Japan (n = 128) and associating them with house dust concentrations and housing characteristics. Detectable concentrations of both diaryl and dialkyl phosphates (DAPs) and hydroxylated metabolites (HO-PFRs) were found in urine samples of almost all children. 2-Hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP) was the most frequently detected metabolite (98%) followed by 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP, 95%) and tris(chloroethyl) phosphate (TCEP). Next to BBOEHEP, two other metabolites of tris(2-butoxyethyl) phosphate (TBOEP) were also frequently detected. Significant correlations of moderate strength were found between parent compounds detected in high concentrations in house dust (TBOEP, tris(2-chloroisopropyl) phosphate (TCIPP)) and their corresponding metabolites, suggesting that dust is a primary exposure source for these PFRs. Several personal and housing characteristics, such as gender, income, and the use of PVC and ventilation were associated with metabolite concentrations in multivariate linear regression. Overall, this study showed that Japanese schoolchildren are exposed to a wide range of PFRs.
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http://dx.doi.org/10.1016/j.envres.2019.02.045DOI Listing
May 2019

Simultaneous determination of 14 urinary biomarkers of exposure to organophosphate flame retardants and plasticizers by LC-MS/MS.

Anal Bioanal Chem 2018 Dec 5;410(30):7871-7880. Epub 2018 Oct 5.

Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Organophosphate flame retardants and plasticizers (PFRs) are a group of chemicals widely added to consumer products. PFRs are quickly metabolized in the human body into two types of metabolites, (1) dialkyl and diaryl phosphate esters (DAPs), such as diphenyl phosphate (DPHP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP); and (2) hydroxylated PFRs (HO-PFRs), such as 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP) and 2-hydroxyethyl bis(2-butoxyethyl) phosphate (BBOEHEP). Existing analytical methods usually focus on DAPs; therefore, human biomonitoring data on HO-PFRs remain scarce. In this study, an analytical procedure was developed for the simultaneous quantification of multiple PFR metabolites in human urine, covering eight DAPs and six HO-PFRs. Sample preparation was optimized to include all target compounds using Bond-Elut C18 solid-phase extraction cartridges, followed by instrumental analysis based on liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). Method performance was validated according to established guidelines and satisfactory results were obtained for all metabolites in terms of recovery, linearity, limits of quantification, precision, and accuracy. Recoveries ranged from 87 to 112%. Method detection limits from 0.002 ng/mL for 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-HO-EHDPHP) to 0.66 ng/mL for 4-hydroxyphenyl phenyl phosphate (4-HO-DPHP). Seven PFR metabolites were frequently detected in a small biomonitoring study (n = 14), among them bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), di-n-butyl phosphate (DNBP), 5-HO-EHDPHP, and BBOEHEP. Highest mean concentrations were found for DPHP, 2-ethylhexyl phenyl phosphate (EHPHP), and BCIPHIPP, while 4-HO-DPHP, 5-HO-EHDPHP, and EHPHP were detected in urine for the first time. Overall, the obtained results demonstrate that the developed method can be used for the simultaneous determination of 14 urinary biomarkers of exposure to PFRs. Graphical abstract ᅟ.
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http://dx.doi.org/10.1007/s00216-018-1402-2DOI Listing
December 2018

Associations between allergic symptoms and phosphate flame retardants in dust and their urinary metabolites among school children.

Environ Int 2018 10 20;119:438-446. Epub 2018 Jul 20.

Hokkaido University Center for Environmental and Health Sciences, Kita 12, Nishi 7, Kita-ku, Sapporo 060-0812, Japan. Electronic address:

Background: Phosphate flame retardants (PFRs) are ubiquitously detected in indoor environments. Despite increasing health concerns pertaining to PFR exposure, few epidemiological studies have examined PFR exposure and its effect on children's allergies.

Objectives: To investigate the association between PFRs in house dust, their metabolites in urine, and symptoms of wheeze and allergies among school-aged children.

Methods: A total of 128 elementary school-aged children were enrolled. House dust samples were collected from upper-surface objects. Urine samples were collected from the first morning void. Levels of 11 PFRs in dust and 14 PFR metabolites in urine were measured. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood questionnaire. The odds ratios (ORs) of the Ln transformed PFR concentrations and categorical values were calculated using a logistic regression model adjusted for sex, grade, dampness index, annual house income, and creatinine level (for PFR metabolites only).

Results: The prevalence rates of wheeze, rhinoconjunctivitis, and eczema were 22.7%, 36.7%, and 28.1%, respectively. A significant association between tris(1,3-dichloroisopropyl) phosphate (TDCIPP) in dust and eczema was observed: OR (95% confidence interval), 1.44 (1.13-1.82) (>limit of detection (LOD) vs LOD vs
Conclusions: We found that TDCIPP in house dust, and metabolites of TDCIPP, TBOEP and TCIPP were associated with children's allergic symptoms. Despite some limitations of this study, these results indicate that children's exposure to PFR may impact their allergic symptoms.
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http://dx.doi.org/10.1016/j.envint.2018.07.018DOI Listing
October 2018

Urinary metabolites of organophosphate esters: Concentrations and age trends in Australian children.

Environ Int 2018 02 28;111:124-130. Epub 2017 Nov 28.

QAEHS, Queensland Alliance for Environmental Health Science, The University of Queensland, 4108 Brisbane, Australia.

There is growing concern around the use of organophosphate esters (OPEs) due to their suspected reproductive toxicity, carcinogenicity, and neurotoxicity. OPEs are used as flame retardants and plasticizers, and due to their extensive application in consumer products, are found globally in the indoor environment. Early life exposure to OPEs is an important risk factor for children's health, but poorly understood. To study age and sex trends of OPE exposures in infants and young children, we collected, pooled, and analysed urine samples from children aged 0-5years from Queensland, Australia for 9 parent OPEs and 11 metabolites. Individual urine samples (n=400) were stratified by age and sex, and combined into 20 pools. Three individual breast milk samples were also analysed to provide a preliminary estimate on the contribution of breast milk to the intake of OPEs. Bis(1-chloroisopropyl) phosphate (BCIPP), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP), bis(1,3-dichloroisopropyl) phosphate (BDCIPP), dibutyl phosphate (DBP), diphenyl phosphate (DPHP), bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate (3OH-TBOEP), and bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were detected in all urine samples, followed by bis(methylphenyl) phosphate (80%), and bis(2-ethylhexyl) phosphate (BEHP, 20%), and bis(2-chloroethyl) phosphate (BCEP, 15%). Concentrations of tris(2-chloroethyl) phosphate (TCEP), BCEP, tris(2-ethylhexyl) phosphate (TEHP), and DBP decreased with age, while bis(methylphenyl) phosphate (BMPP) increased with age. Significantly higher concentrations of DPHP (p=0.039), and significantly lower concentrations of TEHP (p=0.006) were found in female samples compared to males. The estimated daily intakes (EDIs) via breastfeeding, were 4.6, 26 and 76ng/kg/day for TCEP, TBP and TEHP, respectively, and were higher than that via air and dust, suggesting higher exposure through consumption of breast milk.
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http://dx.doi.org/10.1016/j.envint.2017.11.019DOI Listing
February 2018

Probing the relationship between external and internal human exposure of organophosphate flame retardants using pharmacokinetic modelling.

Environ Pollut 2017 Nov 11;230:550-560. Epub 2017 Jul 11.

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-106 91 Stockholm, Sweden.

Human external exposure (i.e. intake) of organophosphate flame retardants (PFRs) has recently been quantified, but no link has yet been established between external and internal exposure. In this study, we used a pharmacokinetic (PK) model to probe the relationship between external and internal exposure data for three PFRs (EHDPHP, TNBP and TPHP) available for a Norwegian cohort of 61 individuals from 61 different households. Using current literature on metabolism of PFRs, we predicted the metabolite serum/urine concentrations and compared it to measured data from the study population. Unavailable parameters were estimated using a model fitting approach (least squares method) after assigning reasonable constraints on the ranges of fitted parameters. Results showed an acceptable comparison between PK model estimates and measurements (<10-fold deviation) for EHDPHP. However, a deviation of 10-1000 was observed between PK model estimates and measurements for TNBP and TPHP. Sensitivity and uncertainty analysis on the PK model revealed that EHDPHP results showed higher uncertainty than TNBP or TPHP. However, there are indications that (1) current biomarkers of exposure (i.e. assumed metabolites) for TNBP and TPHP chemicals might not be specific and ultimately affecting the outcome of the modelling and (2) some exposure pathways might be missing. Further research, such as in vivo laboratory metabolism experiments of PFRs including identification of better biomarkers will reduce uncertainties in human exposure assessment.
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http://dx.doi.org/10.1016/j.envpol.2017.07.002DOI Listing
November 2017

Tailored liquid chromatography-mass spectrometry analysis improves the coverage of the intracellular metabolome of HepaRG cells.

J Chromatogr A 2017 Mar 23;1487:168-178. Epub 2017 Jan 23.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium. Electronic address:

Metabolomics protocols are often combined with Liquid Chromatography-Mass Spectrometry (LC-MS) using mostly reversed phase chromatography coupled to accurate mass spectrometry, e.g. quadrupole time-of-flight (QTOF) mass spectrometers to measure as many metabolites as possible. In this study, we optimised the LC-MS separation of cell extracts after fractionation in polar and non-polar fractions. Both phases were analysed separately in a tailored approach in four different runs (two for the non-polar and two for the polar-fraction), each of them specifically adapted to improve the separation of the metabolites present in the extract. This approach improves the coverage of a broad range of the metabolome of the HepaRG cells and the separation of intra-class metabolites. The non-polar fraction was analysed using a C18-column with end-capping, mobile phase compositions were specifically adapted for each ionisation mode using different co-solvents and buffers. The polar extracts were analysed with a mixed mode Hydrophilic Interaction Liquid Chromatography (HILIC) system. Acidic metabolites from glycolysis and the Krebs cycle, together with phosphorylated compounds, were best detected with a method using ion pairing (IP) with tributylamine and separation on a phenyl-hexyl column. Accurate mass detection was performed with the QTOF in MS-mode only using an extended dynamic range to improve the quality of the dataset. Parameters with the greatest impact on the detection were the balance between mass accuracy and linear range, the fragmentor voltage, the capillary voltage, the nozzle voltage, and the nebuliser pressure. By using a tailored approach for the intracellular HepaRG metabolome, consisting of three different LC techniques, over 2200 metabolites can be measured with a high precision and acceptable linear range. The developed method is suited for qualitative untargeted LC-MS metabolomics studies.
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http://dx.doi.org/10.1016/j.chroma.2017.01.050DOI Listing
March 2017

Does Biotransformation of Aryl Phosphate Flame Retardants in Blood Cast a New Perspective on Their Debated Biomarkers?

Environ Sci Technol 2016 11 4;50(22):12439-12445. Epub 2016 Nov 4.

University of Antwerp, Toxicological Center , Universiteitsplein 1, 2610 Wilrijk, Belgium.

Aryl phosphate flame retardants (aryl-PFRs), such as triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPHP), are emerging contaminants that can exhibit toxic properties, including severe aquatic toxicity and endocrine disruptive effects. Monitoring exposure to aryl-PFRs through specific biomarkers is necessary to assess the health risk associated with chronic exposure. Hydrolytic serum enzymes could play an important role in the formation of the hydrolysis product diphenyl phosphate (DPHP), the seemingly most abundant in vivo biomarker of TPHP in urine. Here, we assess whether serum enzymes have an impact on the toxicokinetics of TPHP and EHDPHP and on the contribution of both aryl-PFRs to in vivo DPHP levels. TPHP and EHDPHP were incubated separately with pooled human serum to measure the formation of hydrolysis products DPHP and 2-ethylhexyl phenyl phosphate (EHPHP) by liquid chromatography-tandem mass spectrometry. Clearance of TPHP and EHDPHP was 70 and 8.6 mL/min/L serum (as measured by formation of DPHP and EHPHP, respectively). No discernible amount of DPHP was produced from EHDPHP by serum hydrolases. Our results suggest that serum hydrolases can significantly contribute to the in vivo levels of DPHP formed from TPHP and can play an important role in the toxicokinetics, toxicity, and selection of biomarkers for aryl-PFRs.
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http://dx.doi.org/10.1021/acs.est.6b03214DOI Listing
November 2016

Stereoselective Metabolism of α-, β-, and γ-Hexabromocyclododecanes (HBCDs) by Human Liver Microsomes and CYP3A4.

Environ Sci Technol 2016 08 25;50(15):8263-73. Epub 2016 Jul 25.

Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Wilrijk, Belgium.

This is the first study investigating the in vitro metabolism of α-, β-, and γ-hexabromocyclododecane (HBCD) stereoisomers in humans and providing semiquantitative metabolism data. Human liver microsomes were incubated with individual racemic mixtures and with individual stereoisomers of α-, β-, and γ-HBCDs, the hydroxylated metabolites formed were analyzed by liquid chromatography-tandem mass spectrometry, and the value of the intrinsic in vitro clearance (Clint,vitro) was calculated. Several mono- and dihydroxylated metabolites of α-, β-, and γ-HBCDs were formed, with mono-OH-HBCDs being the major metabolites. No stereoisomerization of any of the six α-, β-, and γ-HBCD isomers catalyzed by cytochrome P450 (CYP) enzymes occurred. The value of Clint,vitro of α-HBCDs was significantly lower than that of β-HBCDs, which, in turn, was significantly lower than that of γ-HBCDs (p < 0.05). Such differences were explained by the significantly lower values of Clint,vitro of each α-HBCD stereoisomer than those of the β- and γ-HBCD stereoisomers. In addition, significantly lower values of Clint,vitro of the (-) over the (+)α- and β-HBCD stereoisomers, but not γ-HBCDs, were obtained. Our data offer a possible explanation of the enrichment of α-HBCDs over β- and γ-HBCDs on the one hand and, on the other hand, of (-)α-HBCDs over (+)α-HBCDs previously reported in human samples. It also offers information about the mechanism resulting in such enrichments, the stereoisomer-selective metabolism of α-, β-, and γ-HBCDs catalyzed by CYPs with the lack of stereoisomerization.
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http://dx.doi.org/10.1021/acs.est.6b01059DOI Listing
August 2016

Biotransformation of three phosphate flame retardants and plasticizers in primary human hepatocytes: untargeted metabolite screening and quantitative assessment.

J Appl Toxicol 2016 11 18;36(11):1401-8. Epub 2016 Feb 18.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.

Tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP) and tris(1-chloro-2-propyl) phosphate (TCIPP) are current high-volume organophosphate flame retardants/plasticizers (PFRs) and are abundant in the indoor environment. While recent in vitro research has indicated potential toxic effects in the endocrine system, biotransformation of these compounds is still underexplored. In this study, we aimed to characterize the metabolite formation for three PFRs in primary human hepatocytes, an in vitro system that mimics in vivo liver metabolism more closely than hepatic subcellular fractions or cell lines. Cryopreserved human hepatocytes were thawed and suspended in media with 50 μm TBOEP or TCIPP, or 20 μm TPHP up to 2 h. Extracts were analyzed by liquid chromatography-quadrupole-time-of-flight-mass spectrometry. Quantification of biotransformation products in hepatocytes exposed for 2 h revealed that bis(1-chloro-2-propyl) phosphate and diphenyl phosphate corresponded to less than half of the depletion of TCIPP and TPHP, respectively, while bis(2-butoxyethyl) 2-hydroxyethyl phosphate compared to 40-66% of the depletion of TBOEP. Other metabolite structures of these PFRs were produced at 4- to 10-fold lower rates. These findings help interpret biological levels of the major metabolites and relate it to levels of their parent PFR. Percentage of substrate depletion was largest for TBOEP followed by comparable values for TPHP and TCIPP, indicating that hepatic clearance of TPHP and TCIPP would be slower than that of TBOEP. The resulting higher levels and longer presence of TPHP in the circulation after exposure, would allow TPHP a larger time window to exert its suspected adverse effects compared to TBOEP. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jat.3293DOI Listing
November 2016

Impurities of Resorcinol Bis(diphenyl phosphate) in Plastics and Dust Collected on Electric/Electronic Material.

Environ Sci Technol 2016 Feb 29;50(4):1934-40. Epub 2016 Jan 29.

Toxicological Center, University of Antwerp , Universiteitsplein 1, 2610 Antwerp, Wilrijk, Belgium.

Resorcinol bis(diphenylphosphate) (RDP) is an organophosphorus flame retardant widely used in electric and electronic equipment. It has been detected in house dust of several European countries according to recent literature. Similar to other flame retardants, RDP formulations and products treated with RDP, such as plastics, can contain RDP impurities, byproducts and breakdown products. In this study, we use screening methods based on wide scope solvent extraction and high resolution time-of-flight mass spectrometry for the identification of RDP related compounds in products and in dust. We analyzed both plastics from electrical/electronic equipment that contained RDP and indoor dust collected on and around surfaces of this equipment. A variety of compounds, namely TPHP, hydroxylated TPHP and RDP (meta-HO-TPHP and meta-HO-RDP), dihydroxylated TPHP, RDP with the loss of a phenyl group (RDP-[Phe]) and RDP oligomers were detected in plastics containing high levels of RDP. Regarding dust samples collected on electronics, TPHP meta-HO-TPHP, meta-HO-RDP, RDP-[Phe] and RDP oligomers were detected. High concentrations of meta-HO-TPHP (20-14 227 ng/g), TPHP (222-50 728 ng/g) and RDP (23-29 118 ng/g) were found in many of the dust samples, so that these compounds seem to easily migrate into the environment. These RDP impurities, byproducts and breakdown products are for the first time reported in indoor dust. Meta-HO-TPHP could be relevant for future biomonitoring studies concerning flame retardants.
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http://dx.doi.org/10.1021/acs.est.5b05351DOI Listing
February 2016

Effects of primary metabolites of organophosphate flame retardants on transcriptional activity via human nuclear receptors.

Toxicol Lett 2016 Mar 14;245:31-9. Epub 2016 Jan 14.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.

Organophosphate flame retardants (OPFRs) have been used in a wide variety of applications and detected in several environmental matrices, including indoor air and dust. Continuous human exposure to these chemicals is of growing concern. In this study, the agonistic and/or antagonistic activities of 12 primary OPFR-metabolites against ten human nuclear receptors were examined using cell-based transcriptional assays, and compared to those of their parent compounds. As a result, 3-hydroxylphenyl diphenyl phosphate and 4-hydroxylphenyl diphenyl phosphate showed more potent estrogen receptor α (ERα) and ERβ agonistic activity than did their parent, triphenyl phosphate (TPHP). In addition, these hydroxylated TPHP-metabolites also showed ERβ antagonistic activity at higher concentrations and exhibited pregnane X receptor (PXR) agonistic activity as well as androgen receptor (AR) and glucocorticoid receptor (GR) antagonistic activities at similar levels to those of TPHP. Bis(2-butoxyethyl) 3'-hydroxy-2-butoxyethyl phosphate and 2-hydroxyethyl bis(2-butoxyethyl) phosphate act as PXR agonists at similar levels to their parent, tris(2-butoxyethyl) phosphate. On the other hand, seven diester OPFR-metabolites and 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate did not show any receptor activity. Taken together, these results suggest that hydroxylated TPHP-metabolites show increased estrogenicity compared to the parent compound, whereas the diester OPFR-metabolites may have limited nuclear receptor activity compared to their parent triester OPFRs.
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http://dx.doi.org/10.1016/j.toxlet.2016.01.004DOI Listing
March 2016

Kinetics of tris (1-chloro-2-propyl) phosphate (TCIPP) metabolism in human liver microsomes and serum.

Chemosphere 2016 Feb 23;144:1299-305. Epub 2015 Oct 23.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium. Electronic address:

Tris(1-chloro-2-propyl) phosphate (TCIPP) is an emerging contaminant which is ubiquitous in the indoor and outdoor environment. Moreover, its presence in human body fluids and biota has been evidenced. Since no quantitative data exist on the biotransformation or stability of TCIPP in the human body, we performed an in vitro incubation of TCIPP with human liver microsomes (HLM) and human serum (HS). Two metabolites, namely bis(2-chloro-isopropyl) phosphate (BCIPP) and bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), were quantified in a kinetic study using HLM or HS (only BCIPP, the hydrolysis product) and LC-MS. The Michaelis-Menten model fitted best the NADPH-dependent formation of BCIPHIPP and BCIPP in HLM, with respective V(MAX) of 154 ± 4 and 1470 ± 110 pmol/min/mg protein and respective apparent K(m) of 80.2 ± 4.4 and 96.1 ± 14.5 μM. Hydrolases, which are naturally present in HLM, were also involved in the production of BCIPP. A HS paraoxonase assay could not detect any BCIPP formation above 38.6 ± 10.8 pmol/min/μL serum. Our data indicate that BCIPP is the major metabolite of TCIPP formed in the liver. To our knowledge, this is the first quantitative assessment of the stability of TCIPP in tissues of humans or any other species. Further research is needed to confirm whether these biotransformation reactions are associated with a decrease or increase in toxicity.
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http://dx.doi.org/10.1016/j.chemosphere.2015.09.049DOI Listing
February 2016

Metabolomics analysis of the toxicity pathways of triphenyl phosphate in HepaRG cells and comparison to oxidative stress mechanisms caused by acetaminophen.

Toxicol In Vitro 2015 Dec 28;29(8):2045-54. Epub 2015 Aug 28.

Department of In Vitro Toxicology and Dermato-cosmetology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium.

Since the publication of REACH guidelines, the need for in vitro tools for toxicity testing has increased. We present here the development of a hepatotoxicity testing tool using human HepaRG cell cultures and metabolomics. HepaRG cells were exposed to either 4mM acetaminophen (APAP) as reference toxicant for oxidative stress or 50 μM triphenyl phosphate (TPHP) as toxicant with unknown toxicity pathways (TPs). After 72 h exposure, cells were subjected to quenching and liquid-liquid extraction which resulted in a polar and an apolar fraction. Analysis of fractions was performed by ultrahigh performance liquid chromatography-high resolution tandem mass spectrometry (UHPLC-QTOF-MS). Significantly up or down regulated metabolites were selected by univariate statistics prior to identification. In order to obtain robust and specific TP biomarkers, the experiment was also repeated using a different culture medium composition to assess which metabolites show consistent changes. Potential biomarkers belonging to different TPs were found for APAP and TPHP. For APAP, the biomarkers were related to a decrease in unsaturated phospholipids, and for TPHP to an accumulation of phosphoglycerolipids and increase of palmitoyl lysophosphatidylcholine. This first proof-of-concept opens new perspectives for the analysis of other (reference) toxicants with different TPs and it can be used to expand the in vitro tool for hepatotoxicity screening of various compounds.
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http://dx.doi.org/10.1016/j.tiv.2015.08.012DOI Listing
December 2015

In vitro human metabolism of the flame retardant resorcinol bis(diphenylphosphate) (RDP).

Environ Sci Technol 2015 Mar 26;49(6):3897-904. Epub 2015 Feb 26.

†Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Wilrijk, Belgium.

Resorcinol bis(diphenylphosphate) (RDP) is widely used as a flame retardant in electrical/electronic products and constitutes a suitable alternative to decabrominated diphenyl ether. Due to its toxicity and its recently reported ubiquity in electronics and house dust, there are increasing concerns about human exposure to this emerging contaminant. With the aim of identifying human-specific biomarkers, the in vitro metabolism of RDP and its oligomers was investigated using human liver microsomes and human liver cytosol. Mono- and dihydroxy-metabolites, together with glucuronidated and sulfated metabolites, were detected. Regarding RDP oligomers, only a hydroxy-metabolite of the dimer could be detected. RDP and its oligomers were also readily hydrolyzed, giving rise to a variety of compounds, such as diphenyl phosphate, para-hydroxy-triphenyl phosphate, and para-hydroxy RDP, which were further metabolized. These degradation products or impurities are possibly of environmental importance in future studies.
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http://dx.doi.org/10.1021/es505857eDOI Listing
March 2015

In vitro biotransformation of tris(2-butoxyethyl) phosphate (TBOEP) in human liver and serum.

Toxicol Appl Pharmacol 2015 Apr 11;284(2):246-53. Epub 2015 Feb 11.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium. Electronic address:

Tris(2-butoxyethyl) phosphate (TBOEP) is a plasticizer present in indoor dust, reaching levels of several micrograms per gram. Such levels could lead to significant daily exposure of adults and children. Currently, no toxicokinetic data are available to estimate TBOEP clearance in humans after uptake and therefore, one objective of this study was to investigate intrinsic clearance of TBOEP by human liver microsome (HLM) and serum enzymes. Another objective was to generate information to identify and prioritize several metabolites of TBOEP for investigation of human exposure by biomonitoring. 1D and 2D-NMR methodologies were successfully applied on a mixture of the metabolites to confirm the structure of 3-HO-TBOEP (bis(2-butoxyethyl) 3-hydroxyl-2-butoxyethyl phosphate) and to tentatively assign structures to 1-HO-TBOEP and 2-HO-TBOEP. HO-TBOEP isomers and bis(2-butoxyethyl) phosphate (BBOEP), bis(2-butoxyethyl) hydroxyethyl phosphate (BBOEHEP) were further monitored by liquid chromatography-tandem mass spectrometry. Rates of formation of BBOEHEP and HO-TBOEP metabolites by liver enzymes were best described by the Michaelis-Menten model. Apparent Km values for BBOEHEP, 3-HO-TBOEP, and sum of 1- and 2-HO-TBOEP isomer formation were 152, 197 and 148μM, respectively. Apparent Vmax values for the formation of BBOEHEP, 3-HO-TBOEP, and the sum of 1- and 2-HO-TBOEP isomers were 2560, 643, and 254pmol/min/mg protein, respectively. No detectable formation of BBOEP occurred with liver or serum enzymes. Our findings indicate that intrinsic clearance of TBOEP is mainly catalyzed by oxidative enzymes in the liver and that its major in vitro metabolite is BBOEHEP. These findings can be applied in human biomonitoring studies and risk assessment.
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http://dx.doi.org/10.1016/j.taap.2015.01.021DOI Listing
April 2015

In vitro metabolism of 2-ethylhexyldiphenyl phosphate (EHDPHP) by human liver microsomes.

Toxicol Lett 2015 Jan 11;232(1):203-12. Epub 2014 Nov 11.

Toxicological Center, University of Antwerp, Universiteitsplein 1, Antwerp, Wilrijk 2610, Belgium.

2-ethylhexyl diphenyl phosphate (EHDPHP) is used as flame retardant and plasticizer additive in a variety of consumer products. Since EHDPHP is toxic to aquatic organisms and has been detected in environmental samples, concerns about human exposure and toxicity are emerging. With the aim of identifying human-specific metabolites, the biotransformation of EHDPHP was investigated using human liver microsomes. Using an in silico program (Meteor) for the prediction of metabolites, untargeted screening tools (agilent Mass Hunter) and a suitable analysis platform based on ultra-high performance liquid chromatography (UPLC) and quadrupole time-of-flight high resolution mass spectrometer (QTOF-MS), for the first time a wide variety of phases-I and II metabolites of EHDPHP were identified. Mono- and di-hydroxylated metabolites, keto metabolites, mixed keto and hydroxylated metabolites and diphenyl phosphate were the major phase-I metabolites of EHDPHP. Glucuronidated metabolites of phase-I metabolites of EHDPHP were also formed by human liver microsomes. Using these results, we propose a general metabolism pathway for EHDPHP in humans and a number of candidate biomarkers for assessing the human exposure to this ubiquitous phosphate flame retardant and plasticizer in future biomonitoring studies. Furthermore, we provide a template analytical approach based on the combination of untargeted and targeted screening and UPLC-QTOF-MS analysis suitable for use in future metabolism studies.
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http://dx.doi.org/10.1016/j.toxlet.2014.11.007DOI Listing
January 2015

Urinary biomonitoring of phosphate flame retardants: levels in California adults and recommendations for future studies.

Environ Sci Technol 2014 Dec;48(23):13625-33

Silent Spring Institute, 29 Crafts Street, Newton, Massachusetts 02458, United States.

Phosphate flame retardants (PFRs) are abundant and found at the highest concentrations relative to other flame retardant chemicals in house dust; however, little is known about the biological levels of PFRs and their relationship with house dust concentrations. These relationships provide insight into major exposure pathways and potential health risks. We analyzed urine samples from 16 California residents in 2011 for 6 chlorinated and nonchlorinated dialkyl or diaryl phosphates (DAPs), the expected major metabolites of the most prominent PFRs, and qualitatively screened for 18 other metabolites predicted from in vitro studies. We detected all 6 DAPs within the range of previously reported levels, although very few comparisons are available. We found weakly positive nonsignificant correlations between urine and dust concentrations and maxima urine corresponding to maxima dust for the pairs bis(1,3-dichloro-2-propyl) phosphate (BDCIPP)-tris(1,3-dichloro-isopropyl) phosphate (TDCIPP) and bis(2-chloroethyl) phosphate (BCEP)-tris(2-chloroethyl) phosphate (TCEP). Metabolite levels of PFRs were correlated for many PFR combinations, suggesting they commonly co-occur. As far as we know, this is the first study to measure these 6 DAP metabolites simultaneously and to detect other PFR metabolites in US urine samples. We recommend biomonitoring studies include these 6 DAPs as well as several additional compounds detected through qualitative screening and previous ADME studies. PFRs represent a class of poorly studied commercial chemicals with widespread exposure and raise concerns for health effects including carcinogenicity and neurotoxicity.
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http://dx.doi.org/10.1021/es503445cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255275PMC
December 2014

Age as a determinant of phosphate flame retardant exposure of the Australian population and identification of novel urinary PFR metabolites.

Environ Int 2015 Jan 29;74:1-8. Epub 2014 Sep 29.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

The demand for alternative flame retardant materials such as phosphate flame retardants and plasticizers (PFRs) is increasing, although little is known of their possible effects on human health and development. To date, no information on the exposure of children or general Australian population to PFRs is available. The objectives of this study were to characterize the average levels and age-related patterns of PFR metabolites in urine in the general Australian population and to identify novel hydroxylated PFR metabolites in urine. Surplus pathology urine samples from Queensland, Australia were stratified and pooled by age and sex (3224 individuals aged 0 to 75years into 95 pools) according to two different pooling strategies at two different time periods. Samples were analyzed by solid phase extraction and liquid chromatography-tandem mass spectrometry following enzymatic treatment. Nine PFR metabolites were measured in the Australian population, including the first report of a hydroxylated metabolite of TCIPP (BCIPHIPP). Diphenyl phosphate (DPHP), BCIPHIPP and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were detected in >95% of samples. DPHP, a metabolite of aryl-PFRs, was found in several samples at levels which were one order of magnitude higher than previously reported (up to 730ng/mL). Weighted linear regression revealed a significant negative association between log-normalized BDCIPP and DPHP levels and age (p<0.001). Significantly greater levels of BDCIPP and DPHP were found in children's urine compared with adults, suggesting higher exposure to PFRs in young children. BCIPHIPP was identified for inclusion in future PFR biomonitoring studies.
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http://dx.doi.org/10.1016/j.envint.2014.09.005DOI Listing
January 2015

First insights in the metabolism of phosphate flame retardants and plasticizers using human liver fractions.

Toxicol Lett 2013 Oct 27;223(1):9-15. Epub 2013 Aug 27.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Wilrijk, Belgium.

Phosphate flame retardants and plasticizers (PFRs) are additives used in a wide range of polymers. Important representatives, such as tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP), tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), have been found in the indoor environment at high levels. Biotransformation of these PFRs needs to be investigated because it can be a major determinant of their bioavailability and toxicity in humans. TBOEP, TPHP, TCEP, TCIPP and TDCIPP were incubated with human liver S9 fraction and microsomes. Supernatants were analyzed using a liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer. Chromatograms were scanned for the presence of Phase-I and Phase-II metabolites and tentatively identified based on mass accuracy of the molecular formula, isotopic pattern, and MS/MS spectra. The two major metabolites of TBOEP were products of O-dealkylation and of hydroxylation, respectively. TPHP was mainly transformed to its diester metabolite by O-dearylation and to a hydroxylated metabolite. TCEP was poorly metabolized into its diester and a product of oxidative dehalogenation. The major metabolite of TCIPP was a product of oxidative dehalogenation. TDCIPP was mainly transformed into its diester and a glutathione S-conjugate. The metabolites identified in the present study are candidate biomarkers for future human biomonitoring studies.
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http://dx.doi.org/10.1016/j.toxlet.2013.08.012DOI Listing
October 2013

Concentrations of polybrominated diphenyl ethers in matched samples of indoor dust and breast milk in New Zealand.

Environ Int 2013 Sep 10;59:255-61. Epub 2013 Jul 10.

Centre for Public Health Research, Massey University, Wellington 6140, New Zealand.

Polybrominated diphenyl ethers (PBDEs) are present in many consumer goods. There is evidence that PBDEs are toxic to humans, particular young children. The purpose of this study was to assess indoor dust as an exposure source for PBDEs. Concentrations of 16 PBDEs were determined in dust samples from 33 households in New Zealand, and in breast milk samples from 33 mothers living in these households. Associations between dust and breast milk PBDE concentrations were assessed, and children's PBDE intake from breast milk and dust estimated. Influences of household and demographic factors on PBDE concentrations in dust were investigated. Indoor dust concentrations ranged from 0.1ng/g for BDE17 to 2500ng/g for BDE209. Breast milk concentrations were positively correlated (p<0.05) with mattress dust concentrations for BDE47, BDE153, BDE154, and BDE209 and with floor dust for BDE47, BDE183, BDE206, and BDE209. The correlation for BDE209 between dust and breast milk is a novel finding. PBDE concentrations in floor dust were lower from households with new carpets. The estimated children's daily intake of PBDEs from dust and breast milk was below U.S. EPA Reference Dose values. The study shows that dust is an important human exposure source for common PBDE formulations in New Zealand.
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http://dx.doi.org/10.1016/j.envint.2013.06.020DOI Listing
September 2013

Analysis of organophosphate flame retardant diester metabolites in human urine by liquid chromatography electrospray ionisation tandem mass spectrometry.

J Chromatogr A 2013 Aug 26;1303:48-53. Epub 2013 Jun 26.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

A new analytical method was developed for the determination of dialkyl and diaryl phosphates (DAPs), which are metabolites of organophosphate triesters (PFRs), in human urine. Target DAPs included dibutyl phosphate (DBP), diphenyl phosphate (DPHP), bis(2-butoxyethyl) phosphate (BBOEP), bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2-propyl) phosphate (BCPP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). Sample preparation was based on solid phase extraction using a weak anion exchange sorbent (Oasis WAX). Although several instrumental techniques have been tested, best results were obtained with reversed phase liquid chromatography-negative electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) taking the total analysis time into account. Method accuracy at 3ng/mL in pooled urine ranged between 69 and 119% (recovery), while inter-day imprecision (as relative standard deviation) was <31%. The performance of the LC-MS/MS method was compared to a method based on gas chromatography-electron impact tandem mass spectrometry (GC-MS/MS) and a good correlation (Pearson r=0.82, p<0.01) between the results of these two methods was obtained for DPHP. LC-MS/MS analysis was more suitable for DPHP and BBOEP with respective method limits of quantification (mLOQ) of 0.3 and 0.15ng/mL. In contrast, GC-MS/MS had a better sensitivity for BCEP, BCIPP, and BDCIPP, their respective mLOQs being 0.1, 0.06, 0.02ng/mL, compared to 1.2, 3.7, and 0.5ng/mL by LC-MS/MS. A set of urine samples from volunteers was analysed, in which DPHP was the major DAP metabolite. A significant increase of DPHP levels was observed in the group of smokers (geometric mean of 1.55ng/mL) compared to the non-smokers (geometric mean of 0.88ng/mL). Metabolic transformation of triphenyl phosphate to DPHP by metabolic enzymes induced in smokers could be an explanation for this observation.
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http://dx.doi.org/10.1016/j.chroma.2013.06.042DOI Listing
August 2013

After the PBDE phase-out: a broad suite of flame retardants in repeat house dust samples from California.

Environ Sci Technol 2012 Dec 28;46(24):13056-66. Epub 2012 Nov 28.

Silent Spring Institute, 29 Crafts Street, Newton, Massachusetts, USA.

Higher house dust levels of PBDE flame retardants (FRs) have been reported in California than other parts of the world, due to the state's furniture flammability standard. However, changing levels of these and other FRs have not been evaluated following the 2004 U.S. phase-out of PentaBDE and OctaBDE. We analyzed dust collected in 16 California homes in 2006 and again in 2011 for 62 FRs and organohalogens, which represents the broadest investigation of FRs in homes. Fifty-five compounds were detected in at least one sample; 41 in at least 50% of samples. Concentrations of chlorinated OPFRs, including two (TCEP and TDCIPP) listed as carcinogens under California's Proposition 65, were found up to 0.01% in dust, higher than previously reported in the U.S. In 75% of the homes, we detected TDBPP, or brominated "Tris," which was banned in children's sleepwear because of carcinogenicity. To our knowledge, this is the first report on TDBPP in house dust. Concentrations of Firemaster 550 components (EH-TBB, BEH-TEBP, and TPHP) were higher in 2011 than 2006, consistent with its use as a PentaBDE replacement. Results highlight the evolving nature of FR exposures and suggest that manufacturers continue to use hazardous chemicals and replace chemicals of concern with chemicals with uncharacterized toxicity.
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http://dx.doi.org/10.1021/es303879nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3525011PMC
December 2012

A novel abbreviation standard for organobromine, organochlorine and organophosphorus flame retardants and some characteristics of the chemicals.

Environ Int 2012 Nov 13;49:57-82. Epub 2012 Sep 13.

Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, SE-10691 Stockholm, Sweden.

Ever since the interest in organic environmental contaminants first emerged 50years ago, there has been a need to present discussion of such chemicals and their transformation products using simple abbreviations so as to avoid the repetitive use of long chemical names. As the number of chemicals of concern has increased, the number of abbreviations has also increased dramatically, sometimes resulting in the use of different abbreviations for the same chemical. In this article, we propose abbreviations for flame retardants (FRs) substituted with bromine or chlorine atoms or including a functional group containing phosphorus, i.e. BFRs, CFRs and PFRs, respectively. Due to the large number of halogenated and organophosphorus FRs, it has become increasingly important to develop a strategy for abbreviating the chemical names of FRs. In this paper, a two step procedure is proposed for deriving practical abbreviations (PRABs) for the chemicals discussed. In the first step, structural abbreviations (STABs) are developed using specific STAB criteria based on the FR structure. However, since several of the derived STABs are complicated and long, we propose instead the use of PRABs. These are, commonly, an extract of the most essential part of the STAB, while also considering abbreviations previously used in the literature. We indicate how these can be used to develop an abbreviation that can be generally accepted by scientists and other professionals involved in FR related work. Tables with PRABs and STABs for BFRs, CFRs and PFRs are presented, including CAS (Chemical Abstract Service) numbers, notes of abbreviations that have been used previously, CA (Chemical Abstract) name, common names and trade names, as well as some fundamental physico-chemical constants.
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http://dx.doi.org/10.1016/j.envint.2012.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483428PMC
November 2012

Country specific comparison for profile of chlorinated, brominated and phosphate organic contaminants in indoor dust. Case study for Eastern Romania, 2010.

Environ Int 2012 Nov 25;49:1-8. Epub 2012 Aug 25.

Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium.

We have evaluated the levels and specific profiles of several organohalogenated contaminants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and flame retardants (FRs), such as polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDs), novel brominated FRs (NBFRs), and organophosphate FRs (OPFRs), in 47 indoor dust samples collected in 2010 from urban locations from Iasi, Eastern Romania. The dominant contaminants found in the samples were OPFRs (median sum OPFRs 7890 ng/g). Surprisingly, OCPs were also measured at high levels (median 1300 ng/g). Except for BDE 209 (median 275 ng/g), PBDEs were present in dust samples at relatively low levels (median sum PBDEs 8 ng/g). PCBs were also measured at low levels (median sum PCBs 35 ng/g), while NBFRs were only occasionally detected, showing a low usage in goods present on the Romanian market. The results of the present study evidence the existence of a multitude of chemical formulations in indoor dust. FRs are usually associated to human exposure via ingestion of dust, but other chemicals, such as OCPs, are not commonly reported in such matrix. Although OCPs were found at comparable levels with OPFRs in Romanian dust, OCPs possess a higher risk to human health due to their considerably lower reference dose (RfD) values. Indeed, the OCP exposure calculated for various intake scenarios was only 2-fold lower than the corresponding RfD. Therefore, the inclusion of OCPs as target chemicals in the indoor environment becomes important for countries where elevated levels in other environmental compartments have been previously shown.
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http://dx.doi.org/10.1016/j.envint.2012.08.002DOI Listing
November 2012

Concentrations of organophosphate esters and brominated flame retardants in German indoor dust samples.

J Environ Monit 2012 Sep 1;14(9):2482-7. Epub 2012 Aug 1.

School of Geography, Earth, and Environmental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

While it is known that the ingestion of indoor dust contributes substantially to human exposure to the recently restricted polybrominated diphenyl ethers (PBDEs), the situation for one class of potential replacements, i.e. organophosphate esters (OPEs), used in a variety of applications including as flame retardants has yet to be fully characterised. In this study, surface dust from twelve different cars from various locations throughout Germany were analysed for eight OPEs, decabromodiphenyl ethane (DBDPE), and eight PBDEs. In five cars, tris-(1,3-dichloro-2-propyl) phosphate (TDCPP) was the dominant compound with concentrations up to 620 μg g(-1) dust. High concentrations of tri-cresyl phosphate (TCP) (up to 150 μg g(-1)) were also detected in two samples of car dust. Dust from ten offices in the same building in Ludwigsburg, Germany was also analysed. In these samples, tri (2-butoxyethyl) phosphate (TBEP) predominated with an average concentration of 7.0 μg g(-1) dust, followed by tris (1-chloro-2-propyl) phosphate (TCPP) at 3.0 μg g(-1) and triphenyl phosphate (TPhP) at 2.5 μg g(-1) dust. Although caution must be exercised given the relatively small database reported here; this study provides evidence that cars and offices from Germany are significantly more contaminated with OPEs than PBDEs. Average concentrations of ΣOPEs were ten times higher in car than in office dust. This is the first study to provide data on a wide range of OPE concentrations in German indoor dust samples.
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http://dx.doi.org/10.1039/c2em30303eDOI Listing
September 2012

Analytical methods for selected emerging contaminants in human matrices-a review.

Anal Bioanal Chem 2012 Nov 12;404(9):2555-81. Epub 2012 May 12.

Toxicological Centre, University of Antwerp, Wilrijk, Belgium.

Emerging contaminants are a broad category of chemicals, previously unknown or unrecognized as being of concern, but which, because of their potential health effects associated with human exposure, are under increasing scrutiny. To accurately measure their levels in biological matrices, specific and sensitive analytical methods have recently been developed. We have reviewed here the methods used for analysis of selected emerging organic contaminants, for example metabolites of organophosphate triesters, metabolites of new phthalates or phthalate substitutes, perchlorate, organic UV filters, and polycyclic siloxanes, in human matrices. Although the use of new techniques and approaches has been emphasized, we also acknowledge methods previously used for other contaminants and adapted for the emerging contaminants listed above. In all cases, chromatography and mass spectrometry were the techniques of choice, because of their selectivity and sensitivity for measurements at ng g(-1) levels. Critical issues and challenges have been discussed, together with recommendations for further improvement in particular cases (e.g. metabolites of phthalates or their substitutes). In particular, the use of labeled internal standards, the availability of certified reference materials, and the need for interlaboratory comparison exercises are key aspects of further development of this field of research.
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http://dx.doi.org/10.1007/s00216-012-6053-0DOI Listing
November 2012

Occurrence of alternative flame retardants in indoor dust from New Zealand: indoor sources and human exposure assessment.

Chemosphere 2012 Sep 30;88(11):1276-82. Epub 2012 Apr 30.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

Due to worldwide restrictions on polybrominated diphenyl ethers (PBDEs), the demand for alternative flame retardants (AFRs), such as organophosphate flame retardants (OPFRs), novel brominated FRs (NBFRs) and hexabromocyclododecanes (HBCDs), has recently increased. Little is known about human exposure to NBFRs and OPFRs and that their levels in dust have been scarcely evaluated worldwide. To increase the knowledge regarding these chemicals, we measured concentrations of five major NBFRs, ten OPFRs and three HBCD isomers in indoor dust from New Zealand homes. Dust samples were taken from living room floors (n=34) and from mattresses of the same houses (n=16). Concentrations (ngg(-1)) of NBFRs were: 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) (<2-175), decabromodiphenyl ethane (DBDPE) (<5-1430), 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) (<2-2285) and bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (TBPH) (<2-640). For OPFRs, concentrations (ngg(-1)) ranged between: tri-ethyl-phosphate (TEP) (<10-235), tri-n-butyl-phosphate (TnBP) (<20-7545), tris-(2-chloroethyl)-phosphate (TCEP) (<20-7605), tris-(1-chloro-2-propyl) phosphate (TCPP) (20-7615), tri-(2-butoxyethyl)-phosphate (TBEP) (50-27325), tris-(2,3-dichloropropyl)-phosphate (TDCPP) (20-16560), tri-phenyl-phosphate (TPhP) (20-35190), and tri-cresyl-phosphate (TCP) (<50-3760). HBCD concentrations fell in the range <2-4100ngg(-1). BTBPE, DBDPE, TBPH, TBEP, and TnBP showed significant positive correlation (p<0.05) between their concentrations in mattresses and the corresponding floor dust (n=16). These data were used to derive a range of plausible exposure scenarios. Although the estimated exposure is well below the corresponding reference doses (RfDs), caution is needed given the likely future increase in use of these FRs and the currently unknown contribution to human exposure by other pathways such as inhalation and diet.
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http://dx.doi.org/10.1016/j.chemosphere.2012.03.100DOI Listing
September 2012
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