| 1. |
- Hendriks, Hester S., et al.
(author)
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Effects on neonatal exposure to the flame retardant tetrabrombisphenol-A, aluminum diethylphosphinate or zinc stannate on long-term, potentiation and synaptic protein levels in mice
- 2015
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In: Archives of Toxicology. - : Springer Nature. - 0340-5761 .- 1432-0738. ; 89:12, s. 2345-2354
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Journal article (peer-reviewed)abstract
- Brominated flame retardants such as tetrabromobisphenol-A (TBBPA) may exert (developmental) neurotoxic effects. However, data on (neuro)toxicity of halogen-free flame retardants (HFFRs) are scarce. Recent in vitro studies indicated a high neurotoxic potential for some HFFRs, e.g., zinc stannate (ZS), whereas the neurotoxic potential of other HFFRs, such as aluminum diethylphosphinate (Alpi), appears low. However, the in vivo (neuro)toxicity of these compounds is largely unknown. We therefore investigated effects of neonatal exposure to TBBPA, Alpi or ZS on synaptic plasticity in mouse hippocampus. Male C57bl/6 mice received a single oral dose of 211 µmol/kg bw TBBPA, Alpi or ZS on postnatal day (PND) 10. On PND 17–19, effects on hippocampal synaptic plasticity were investigated using ex vivo extracellular field recordings. Additionally, we measured levels of postsynaptic proteins involved in long-term potentiation (LTP) as well as flame retardant concentrations in brain, muscle and liver tissues. All three flame retardants induced minor, but insignificant, effects on LTP. Additionally, TBBPA induced a minor decrease in post-tetanic potentiation. Despite these minor effects, expression of selected synaptic proteins involved in LTP was not affected. The flame retardants could not be measured in significant amounts in the brains, suggesting low bioavailability and/or rapid elimination/metabolism. We therefore conclude that a single neonatal exposure on PND 10 to TBBPA, Alpi or ZS does affect neurodevelopment and synaptic plasticity only to a small extent in mice. Additional data, in particular on persistence, bioaccumulation and (in vivo) toxicity, following prolonged (developmental) exposure are required for further (human) risk assessment.
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| 2. |
- Lupu, Diana, et al.
(author)
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The ENDpoiNTs Project : Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity
- 2020
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In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:11
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Journal article (peer-reviewed)abstract
- Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing. This will be achieved by establishing correlative and causal links between known and novel neurodevelopmental endpoints and endocrine pathways through integration of molecular, cellular, and organismal data from in vitro and in vivo models. Based on this knowledge, the project aims to provide adverse outcome pathways (AOPs) for ED-induced DNT and to develop and integrate new testing tools with high relevance for human health into European and international regulatory frameworks.
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| 3. |
- Waaijers, Susanne L., et al.
(author)
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Persistence, Bioaccumulation, and Toxicity of Halogen-Free Flame Retardants
- 2013
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In: Reviews of Environmental Contamination and Toxicology. - New York, NY : Springer. - 9781461447160 - 9781461447177 ; , s. 1-71
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Book chapter (peer-reviewed)abstract
- Polymers are synthetic organic materials having a high carbon and hydrogen content, which make them readily combustible. Polymers have many indoor uses and their flammability makes them a fire hazard. Therefore, flame retardants (FRs) are incorporated into these materials as a safety measure. Brominated flame retardants (BFRs), which accounted for about 21% of the total world market of FRs, have several unintended negative effects on the environment and human health. Hence, there is growing interest in finding appropriate alternative halogen-free flame retardants (HFFRs). Many of these HFFRs are marketed already, although their environ- mental behavior and toxicological properties are often only known to a limited extent, and their potential impact on the environment cannot yet be properly assessed. Therefore, we undertook this review to make an inventory of the available data that exists (up to September 2011) on the physical-chemical properties, pro- duction volumes, persistence, bioaccumulation, and toxicity (PBT) of a selection of HFFRs that are potential replacements for BFRs in polymers. Large data gaps were identified for the physical-chemical and the PBT properties of the reviewed HFFRs. Because these HFFRs are currently on the market, there is an urgent need to fill these data gaps. Enhanced transparency of methodology and data are needed to reevaluate certain test results that appear contradictory, and, if this does not provide new insights, further research should be performed. TPP has been studied quite extensively and it is clearly persistent, bioaccumulative, and toxic. So far, RDP and BDP have demonstrated low to high ecotoxicity and persistence. The compounds ATH and ZB exerted high toxicity to some species and ALPI appeared to be persistent and has low to moderate reported ecotoxicity. DOPO and MPP may be persistent, but this view is based merely on one or two studies, clearly indicating a lack of information. Many degradation studies have been performed on PER and show low persistence, with a few exceptions. Additionally, there is too l ittle information on the bioaccumulation potential of PER. APP mostly has low PBT properties; however, moderate ecotoxicity was reported in two studies. Mg(OH)₂, ZHS, and ZS do not show such remarkably high bioaccumulation or toxicity, but large data gaps exist for these compounds also. Nevertheless, we consider the latter compounds to be the most promising among alternative HFFRs. To assess whether the presently reviewed HFFRs are truly suitable alternatives, each compound should be examined individually by comparing its PBT values with those of the relevant halogenated flame retardant. Until more data are available, it remains impossible to accurately evaluate the risk of each of these compounds, including the ones that are already extensively marketed.
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| 4. |
- Alves, Andreia, et al.
(author)
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Case Study on Screening Emerging Pollutants in Urine and Nails
- 2017
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 51:7, s. 4046-4053
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Journal article (peer-reviewed)abstract
- Alternative plasticizers and flame retardants (FRs) have been introduced as replacements for banned or restricted chemicals, but much is still unknown about their metabolism and occurrence in humans. We identified the metabolites formed in vitro for four alternative plasticizers (acetyltributyl citrate (ATBC), bis(2-propylheptyl) phthalate (DPHP), bis(2-ethylhexyl) terephthalate (DEHTP), bis(2ethylhexyl) adipate (DEHA)), and one FR (2,2-bis (chloromethyl)-propane-1,3-diyltetrakis(2-chloroethyl) bisphosphate (V6)). Further, these compounds and their metabolites were investigated by LC/ESI-Orbitrap-MS in urine and finger nails collected from a Norwegian cohort. Primary and secondary ATBC metabolites had detection frequencies (% DF) in finger nails ranging from 46 to 95%. V6 was identified for the first time in finger nails, suggesting that this matrix may also indicate past exposure to FRs as well as alternative plasticizers. Two isomeric forms of DEHTP primary metabolite were highly detected in urine (97% DF) and identified in finger nails, while no DPHP metabolites were detected in vivo. Primary and secondary DEHA metabolites were identified in both matrices, and the relative proportion of the secondary metabolites was higher in urine than in finger nails; the opposite was observed for the primary metabolites. As many of the metabolites present in in vitro extracts were further identified in vivo in urine and finger nail samples, this suggests that in vitro assays can reliably mimic the in vivo processes. Finger nails may be a useful noninvasive matrix for human biomonitoring of specific organic contaminants, but further validation is needed.
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| 5. |
- Audouze, Karine, et al.
(author)
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Evidenced-Based Approaches to Support the Development of Endocrine-Mediated Adverse Outcome Pathways : Challenges and Opportunities
- 2021
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In: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 3
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Journal article (peer-reviewed)abstract
- A transformation of regulatory toxicology is underway to meet the demands of testing increasing numbers of chemicals whilst reducing reliance on in vivo models. This transformation requires a shift from chemical safety assessment largely based on direct empirical observation of apical toxicity outcomes in whole organisms to predictive approaches in which outcomes and risks are inferred from accumulated mechanistic understanding.
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| 6. |
- Brandsma, Sicco H., et al.
(author)
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Two organophosphorus flame retardants, resorcinol bis (diphenylphosphate)(PBDPP) and bisphenol A bis (diphenylphosphate) (BPA-BDPP) used as alternatives for BDE209 detected in dust
- 2013
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 1086-931X .- 1520-6912 .- 0013-936X .- 1520-5851. ; 47:24, s. 14434-14441
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Journal article (peer-reviewed)abstract
- Resorcinol bis(diphenylphosphate) (RBDPP) and bisphenol A bis(diphenylphosphate) (BPA-BDPP) are two halogen-free organophosphorus flame retardant (PFRs) that are used as an alternative for the decabromodiphenyl ether (Deca-BDE) technical mixture in TV/flatscreen housing and other electronic consumer products.' In this study, dust samples were collected from various microenvironments in The Netherlands (houses, cars), Greece.(houses), and Sweden (apartments, cars, furniture stores, electronics stores) and analyzed for RBDPP and BPA-BDPP. Additionally, the dust samples from The Netherlands were analyzed for decabromodiphenyl ether (BDE-209) for comparison and for TPHP, which is a byproduct in the RBDPP and BPA-BDPP technical products. BPA-BDPP was detected in almost all dust samples from The Netherlands, Greece, and Sweden. Highest concentrations were found in dust samples collected on electronic equipment from all three countries with BPA-BDPP levels ranging from <0.1 to 1300 mu g/g and RBDPP levels from <0.04 to 520 mu g/g. RBDPP and BPA-BDPP levels in dust collected further away from the electronics (source) were usually lower. BDE-209 levels in The Netherlands dust samples collected on and around the electronics were similar and much lower than the BPA-BDPP/RBDPP levels, indicating that the electronics were not the source of BDE-209. Strong positive correlations were found between TPHP concentrations and those of RBDPP (r = 0.805) and BPA-BDPP (r = 0.924), probably due to TPHP being a byproduct in commercial RBDPP and BPA-BDPP mixtures in electronics. To our knowledge, this is the first time that RBDPP and BPA-BDPP were detected in dust samples from Europe.
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| 7. |
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| 8. |
- Gustafsson, Johan, 1991-
(author)
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Exposure and effects of naturally produced hydroxylated polybrominated diphenyl ethers in fish : Implications for Baltic Sea wildlife
- 2022
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Doctoral thesis (other academic/artistic)abstract
- The aim of this thesis was to investigate if naturally produced hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are causing negative health effects for Baltic Sea wildlife. In the laboratory, OH-PBDEs have shown to be potent disrupters of energy metabolism as well as endocrine disruptors and neurotoxins. OH-PBDEs are naturally produced, for example, by filamentous macroalgae in the Baltic Sea but are also metabolites of the flame retardants polybrominated diphenyl ethers (PBDEs). High concentrations of OH-PBDEs have been detected in several species in the Baltic Sea, including the European perch (Perca fluviatilis). The concentrations of OH-PBDEs in perch, and some other species from the Baltic Sea, are within reported toxicological effect concentrations.In this thesis, perch were sampled approximately once a week during an exposure peak of OH-PBDEs between May and October in 2018. In Paper I, correlations between OH-PBDEs and several health biomarkers in perch were studied. A higher OH-PBDE concentration correlated with increased ethoxyresorufin-O-deethylase (EROD) activity, increased plasma lactate concentration, increased plasma glucose concentration, decreased lipid percentage in muscle, and decreased liver somatic index. These correlations indicate that OH-PBDEs might cause negative health effects in perch from the Baltic Sea.Many aquatic species in the Baltic Sea have been reported to suffer from thiamine (vitamin B1) deficiency. Thiamine deficiency could be a confounding factor when assessing potential in vivo effects of OH-PBDEs. Hence, in Paper II, the thiamine status of perch was investigated. Perch were found to have sufficient thiamine, thus thiamine deficiency is not a confounding factor when assessing potential effects of OH-PBDEs in perch from the Baltic Sea.In Paper III, metabolomics was performed on zebrafish (Danio rerio) embryos exposed to OH-PBDEs. The aim was to study the toxicity of OH-PBDEs at the metabolome level and to identify selective and sensitive biomarker(s) for energy disruption of OH-PBDEs. OH-PBDEs were found to cause diverse metabolic effects at environmentally relevant concentrations. Accumulation of succinic acid, a key metabolite for energy production and regulation of the immune system, was suggested as a potential biomarker for energy disruption due to OH-PBDEs. In Paper IV, lipids and 19 polar metabolites, including metabolites observed to be affected by OH-PBDEs in Paper III, were analysed in perch from the Baltic Sea. Among other findings, a correlation between increased OH-PBDE exposure and increased concentration of succinic acid was observed. The correlations observed in the perch to a large extent agreed with the metabolic effects seen in zebrafish embryos exposed to OH-PBDEs (Paper III), indicating potential causality between exposure to OH-PBDEs and effects in perch from the Baltic Sea.The correlations observed in this thesis between OH-PBDEs and biomarkers in perch should be interpreted with caution as the correlations could be spurious, for example caused by underlying environmental factors. However, taken together, the results support the hypothesis that naturally produced OH-PBDEs could cause negative health effects in perch from the Baltic Sea.
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| 9. |
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| 10. |
- Gustafsson, Johan, et al.
(author)
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Metabolite alterations in zebrafish embryos exposed to hydroxylated polybrominated diphenyl ethers
- 2023
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In: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 857
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Journal article (peer-reviewed)abstract
- Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are formed by metabolism from the flame retardants polybrominated diphenyl ethers (PBDEs). In the aquatic environment, they are also produced naturally. OH-PBDEs are known for their potential to disrupt energy metabolism, the endocrine system, and the nervous system. This is the first study focusing on the effects of OH-PBDEs at the metabolite level in vivo. The aim of the current study was to investigate the metabolic effects of exposure to OH-PBDEs using metabolomics, and to identify potential biomarker(s) for energy disruption of OH-PBDEs. Zebrafish (Danio rerio) embryos were exposed to two different concentrations of 6-OH-BDE47 and 6-OH-BDE85 and a mixture of these two compounds. In total, 342 metabolites were annotated and 79 metabolites were affected in at least one exposure. Several affected metabolites, e.g. succinic acid, glutamic acid, glutamine, tyrosine, tryptophan, adenine, and several fatty acids, could be connected to known toxic mechanisms of OH-PBDEs. Several phospholipids were strongly up-regulated with up to a six-fold increase after exposure to 6-OH-BDE47, a scarcely described effect of OH-PBDEs. Based on the observed metabolic effects, a possible connection between disruption of the energy metabolism, neurotoxicity and potential immunotoxicity of OH-PBDEs was suggested. Single compound exposures to 6-OH-BDE47 and 6-OH-BDE85 showed little overlap in the affected metabolites. This shows that compounds of similar chemical structure can induce different metabolic effects, possibly relating to their different toxic mechanisms. There were inter-concentration differences in the metabolic profiles, indicating that the metabolic effects were concentration dependent. After exposure to the mixture of 6-OH-BDE47 and 6-OH-BDE85, a new metabolic profile distinct from the profiles obtained from the single compounds was observed. Succinic acid was up-regulated at the highest, but still environmentally relevant, concentration of 6-OH-BDE47, 6-OH-BDE85, and the mixture. Therefore, succinic acid is suggested as a potential biomarker for energy disruption of OH-PBDEs.
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