| 1. |
- Waaijers, Susanne L., et al.
(författare)
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Persistence, Bioaccumulation, and Toxicity of Halogen-Free Flame Retardants
- 2013
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Ingår i: Reviews of Environmental Contamination and Toxicology. - New York, NY : Springer. - 9781461447160 - 9781461447177 ; , s. 1-71
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Bokkapitel (refereegranskat)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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| 2. |
- Dingemans, Milou M. L., et al.
(författare)
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Bromination Pattern of Hydroxylated Metabolites of BDE-47 Affects Their Potency to Release Calcium from Intracellular Stores in PC12 Cells
- 2010
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 118:4, s. 519-525
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Brominated flame retardants, including the widely used polybrominated diphenyl ethers (PBDEs), have been detected in humans, raising concern about possible neurotoxicity. Recent research demonstrated that the hydroxylated metabolite 6-OH-BDE-47 increases neurotransmitter release by releasing calcium ions (Ca2+) from intracellular stores at much lower concentrations than its environmentally relevant parent congener BDE-47. Recently, several other hydroxylated BDE-47 metabolites, besides 6-OH-BDE-47, have been detected in human serum and cord blood. OBJECTIVE AND METHODS: To investigate the neurotoxic potential of other environmentally relevant PBDEs and their metabolites, we examined and compared the acute effects of BDE-47, BDE-49, BDE-99, BDE-100, BDE-153, and several metabolites of BDE-47-6-OH-BDE-47 (and its methoxylated analog 6-MeO-BDE-47), 6'-OH-BDE-49, 5-OH-BDE-47, 3-OH-BDE-47, and 4'-OH-BDE-49 on intracellular Ca2+ concentration ([Ca2+](i)), measured using the Ca2+-responsive dye Fura-2 in neuroendocrine pheochromocytoma (PC12) cells. RESULTS: In contrast to the parent PBDEs and 6-MeO-BDE-47, all hydroxylated metabolites induced Ca2+ release from intracellular stores, although with different lowest observed effect concentrations (LOECs). The major intracellular Ca2+ sources were either endoplasmic reticulum (ER; 5-OH-BDE-47 and 6'-OH-BDE-49) or both ER and mitochondria (6-OH-BDE-47, 3-OH-BDE-47, and 4'-OH-BDE-49). When investigating fluctuations in [Ca2+](i), which is a more subtle end point, we observed lower LOECs for 6-OH-BDE-47 and 4'-OH-BDE-49, as well as for BDE-47. CONCLUSIONS: The present findings demonstrate that hydroxylated metabolites of BDE-47 cause disturbance of the [Ca2+](i). Importantly, shielding of the OH group on both sides with bromine atoms and/or the ether bond to the other phenyl ring lowers the potency of hydroxylated PBDE metabolites.
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| 3. |
- Dingemans, Milou M. L., et al.
(författare)
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Calcium-Related Processes Involved in the Inhibition of Depolarization-Evoked Calcium Increase by Hydroxylated PBDEs in PC12 Cells
- 2010
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 114:2, s. 302-309
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Tidskriftsartikel (refereegranskat)abstract
- In vitro studies indicated that hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have an increased toxic potential compared to their parent congeners. An example is the OH-PBDE–induced increase of basal intracellular Ca2+ concentration ([Ca2+]i) by release of Ca2+ from endoplasmic reticulum (ER) and mitochondria and/or influx of extracellular Ca2+. ER and mitochondria regulate Ca2+ homeostasis in close association with voltage-gated Ca2+ channels (VGCCs). Therefore, effects of (OH-)PBDEs on the depolarization-evoked (100mM K+) net increase in [Ca2+]i (depolarization-evoked [Ca2+]i) were measured in neuroendocrine pheochromocytoma cells using the Ca2+-responsive dye Fura-2. OH-PBDEs dose dependently inhibited depolarization-evoked [Ca2+]i. This inhibition was potentiated by a preceding increase in basal [Ca2+]i. Especially at higher concentrations of OH-PBDEs (5–20μM), large increases in basal [Ca2+]i strongly inhibited depolarization-evoked [Ca2+]i. The inhibition appeared more sensitive to increases in basal [Ca2+]i by Ca2+ release from intracellular stores (by 3-OH-BDE-47 or 6′-OH-BDE-49) compared to those by influx of extracellular Ca2+ (by 6-OH-BDE-47 or 5-OH-BDE-47). The expected [Ca2+]i difference close to the membrane suggests involvement of Ca2+-dependent regulatory processes close to VGCCs. When coapplied with depolarization, some OH-PBDEs induced also moderate direct inhibition of depolarization-evoked [Ca2+]i. Polybrominated diphenyl ethers and methoxylated BDE-47 affected neither basal nor depolarization-evoked [Ca2+]i, except for BDE-47, which moderately increased fluctuations in basal [Ca2+]i and depolarization-evoked [Ca2+]i. These findings demonstrate that OH-PBDEs inhibit depolarization-evoked [Ca2+]i depending on preceding basal [Ca2+]i. Related environmental pollutants that affect Ca2+ homeostasis (e.g., polychlorinated biphenyls) may thus also inhibit depolarization-evoked [Ca2+]i, justifying further investigation of possible mixture effects of environmental pollutants on Ca2+ homeostasis.
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| 4. |
- Dingemans, Milou M. L., et al.
(författare)
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Hexabromocyclododecane Inhibits Depolarization-Induced Increase in Intracellular Calcium Levels and Neurotransmitter Release in PC12 Cells
- 2009
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 107:2, s. 490-497
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Tidskriftsartikel (refereegranskat)abstract
- Environmental levels of the brominated flame retardant (BFR) hexabromocyclododecane (HBCD) have been increasing. HBCD has been shown to cause adverse effects on learning and behavior in mice, as well as on dopamine uptake in rat synaptosomes and synaptic vesicles. For other BFRs, alterations in the intracellular Ca2+ homeostasis have been observed. Therefore, the aim of this study was to investigate whether the technical HBCD mixture and individual stereoisomers affect the intracellular Ca2+ concentration ([Ca2+](i)) in a neuroendocrine in vitro model (PC12 cells). [Ca2+](i) and vesicular catecholamine release were measured using respectively single-cell Fura-2 imaging and amperometry. Exposure of PC12 cells to the technical HBCD mixture or individual stereoisomers did neither affect basal [Ca2+](i), nor the frequency of basal neurotransmitter release. However, exposure to HBCD (0-20 mu M) did cause a dose-dependent reduction of a subsequent depolarization-evoked increase in [Ca2+](i). This effect was apparent only when HBCD was applied at least 5 min before depolarization (maximum effect after 20 min exposure). The effects of alpha- and beta-HBCD were comparable to that of the technical mixture, whereas the inhibitory effect of gamma-HBCD was larger. Using specific blockers of L-, N- or P/Q-type voltage-gated Ca2+ channels (VGCCs) it was shown that the inhibitory effect of HBCD is not VGCC-specific. Additionally, the number of cells showing depolarization-evoked neurotransmitter release was markedly reduced following HBCD exposure. Summarizing, HBCD inhibits depolarization-evoked [Ca2+](i) and neurotransmitter release. As increasing HBCD levels should be anticipated, these findings justify additional efforts to establish an adequate exposure, hazard and risk assessment.
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| 5. |
- Dingemans, Milou M L, et al.
(författare)
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Hydroxylation increases the neurotoxic potential of BDE-47 to affect exocytosis and calcium homeostasis in PC12 cells.
- 2008
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 116:5, s. 637-43
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Oxidative metabolism, resulting in the formation of hydroxylated polybrominated diphenyl ether (PBDE) metabolites, may enhance the neurotoxic potential of brominated flame retardants. OBJECTIVE: Our objective was to investigate the effects of a hydroxylated metabolite of 2,2',4,4'-tetra-bromodiphenyl ether (BDE-47; 6-OH-BDE-47) on changes in the intracellular Ca2+ concentration ([Ca2+]i) and vesicular catecholamine release in PC12 cells. METHODS: We measured vesicular catecholamine release and [Ca2+]i using amperometry and imaging of the fluorescent Ca2+-sensitive dye Fura-2, respectively. RESULTS: Acute exposure of PC12 cells to 6-OH-BDE-47 (5 microM) induced vesicular catecholamine release. Catecholamine release coincided with a transient increase in [Ca2+]i, which was observed shortly after the onset of exposure to 6-OH-BDE-47 (120 microM). An additional late increase in [Ca2+]i was often observed at > or =1 microM 6-OH-BDE-47. The initial transient increase was absent in cells exposed to the parent compound BDE-47, whereas the late increase was observed only at 20 microM. Using the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and thapsigargin to empty intracellular Ca2+ stores, we found that the initial increase originates from emptying of the endoplasmic reticulum and consequent influx of extracellular Ca2+, whereas the late increase originates primarily from mitochondria. CONCLUSION: The hydroxylated metabolite 6-OH-BDE-47 is more potent in disturbing Ca2+ homeostasis and neurotransmitter release than the parent compound BDE-47. The present findings indicate that bioactivation by oxidative metabolism adds considerably to the neurotoxic potential of PBDEs. Additionally, based on the observed mechanism of action, a cumulative neurotoxic effect of PBDEs and ortho-substituted polychlorinated biphenyls on [Ca2+]i cannot be ruled out.
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| 6. |
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| 7. |
- Fernandes, Elsa C Antunes, et al.
(författare)
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Activation and potentiation of human GABAA receptors by non-dioxin-like PCBs depends on chlorination pattern
- 2010
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 118:1, s. 183-90
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Tidskriftsartikel (refereegranskat)abstract
- The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABA(A) receptors. In the present study, effects of 20 NDL-PCBs and 2 dioxin-like PCBs, selected based on their chemical variation and abundance in the environment, on human GABA(A) receptors were investigated. GABA(A) receptors were expressed in Xenopus oocytes, and NDL-PCB effects were determined using the two-electrode voltage-clamp technique. Results demonstrate that lower chlorinated PCB19, PCB28, PCB47, PCB51, PCB52, PCB95, and PCB100 act as a partial agonists (at low receptor occupancy), i.e., potentiating the receptor response during coapplication with GABA (at EC(20)). Importantly, PCB19, PCB47, PCB51, and PCB100 can also act as full agonist, i.e., activate the GABA(A) receptor in the absence of GABA. Potentiation and activation of the GABA(A) receptor is concentration dependent and limited to NDL-PCBs that have 3-5 chlorine atoms, 1-3 ortho-substitutions, an equal number (0-1) of meta-substitutions on both phenyl rings, and do not have an adjacent para- and meta-substitution on the same phenyl ring. Activation and potentiation of the GABA(A) receptor by PCB47, the most potent congener (lowest observed effect concentration of 10nM), is attenuated when coapplied with PCB19, PCB28, PCB153, or PCB180, indicative for competitive binding. Considering the importance of GABA-ergic signaling for brain development, motor coordination, learning, and memory, this mode of action can contribute to the previously observed NDL-PCB-induced neurobehavioral and neurodevelopmental effects and should be included in human risk assessment.
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| 8. |
- Gassmann, Kathrin, et al.
(författare)
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BDE-47 and 6-OH-BDE-47 modulate calcium homeostasis in primary fetal human neural progenitor cells via ryanodine receptor-independent mechanisms
- 2014
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 88:8, s. 1537-1548
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Tidskriftsartikel (refereegranskat)abstract
- Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants found in rising concentrations in human tissue. Epidemiological and animal studies have raised concern for their potential to induce developmental neurotoxicity (DNT). Considering the essential role of calcium homeostasis in neurodevelopment, PBDE-induced disturbance of intracellular calcium concentration ([Ca2+](i)) may underlie PBDE-induced DNT. To test this hypothesis, we investigated acute effects of BDE-47 and 6-OH-BDE-47 on [Ca2+](i) in human neural progenitor cells (hNPCs) and unraveled involved signaling pathways. Short-time differentiated hNPCs were exposed to BDE-47, 6-OH-BDE-47, and multiple inhibitors/stimulators of presumably involved signaling pathways to determine possible effects on [Ca2+](i) by single-cell microscopy with the fluorescent dye Fura-2. Initial characterization of calcium signaling pathways confirmed the early developmental stage of hNPCs. In these cells, BDE-47 (2 mu M) and 6-OH-BDE-47 (0.2 mu M) induce [Ca2+](i) transients. This increase in [Ca2+](i) is due to extracellular Ca2+ influx and intracellular release of Ca2+, mainly from the endoplasmic reticulum (ER). While extracellular Ca2+ seems to enter the cytoplasm upon 6-OH-BDE-47 by interfering with the cell membrane and independent of Ca2+ ion channels, ER-derived Ca2+ is released following activation of protein lipase C and inositol 1,4,5-trisphosphate receptor, but independently of ryanodine receptors. These findings illustrate that immature developing hNPCs respond to low concentrations of 6-OH-BDE-47 by an increase in [Ca2+](i) and provide new mechanistic explanations for such BDE-induced calcium disruption. Thus, these data support the possibility of a critical window of PBDE exposure, i.e., early human brain development, which has to be acknowledged in risk assessment.
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| 9. |
- Hendriks, Hester S., et al.
(författare)
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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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Ingår i: Archives of Toxicology. - : Springer Nature. - 0340-5761 .- 1432-0738. ; 89:12, s. 2345-2354
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Tidskriftsartikel (refereegranskat)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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| 10. |
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