Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. ...Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABAA neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABAA receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABAA and excitatory α4β2 nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABAA receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABAA receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABAA and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABAA-mediated signaling being potentiated and excitatory α4β2 nACh–mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.
This study investigates exposure to polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBPA), which are used as flame retardants in electronic equipment, in a group of technicians ...with intense computer work.
Thirteen PBDE congeners and TBBPA were quantified in serum from 19 computer technicians. Previously investigated groups of hospital cleaners with no computer experience, and clerks working full-time at computer screens were used for comparison. The computer technicians had serum concentrations of BDE-153, BDE-183 and BDE-209 that were five times higher than those reported among hospital cleaners and computer clerks. The median levels observed among the computer technicians were 4.1, 1.3, and 1.6 pmol/g lipid weight, respectively. In contrast, for BDE-47 there was no difference between the computer technicians and the others.
BDE-100, BDE-203, and three structurally unidentified octa-BDEs and three nona-BDEs, were present in almost all samples from the computer technicians. Further, TBBPA was detected in 8 out of 10 samples. The levels of BDE-153, BDE-183, and one of the octa-BDEs were positively correlated with duration of computer work among technicians.
On a group level an exposure gradient was observed, from the least exposed cleaners to the clerks, and to the highest exposed group of computer technicians. A dose (duration of computer work)–response relationship among computer technicians was demonstrated for some higher brominated PBDE congeners. Thus, it is evident that PBDEs used in computers and electronics, including the fully brominated BDE-209, contaminate the work environment and accumulate in the workers tissues.
Bioaccumulation of persistent organic compounds can eventually lead to concentrations in wildlife and humans that are deleterious to health. The present paper documents the identification, ...quantification, and synthesis of a novel compound, 2,2‘-dimethoxy-3,3‘,5,5‘-tetrabromobiphenyl (2,2‘-diMeO-BB80), present in the marine mammals Striped dolphin (Stenella coeruleoalba), Bottlenose dolphin (Tursiops truncatus), Minke whale (Balaenoptera acutorostrata), and Baird's beaked whale (Berardius bairdii) caught in the Pacific Ocean. Identification was based on comparison of the relative retention times of the compound on two gas chromatographic columns of different polarities to those of an authentic standard. Furthermore, this identification was also supported by comparison of the full scan mass spectrometric data collected employing electron ionization (EI), positive ion chemical ionization (PICI), and electron capture negative ionization (ECNI). The concentrations of 2,2‘-diMeO-BB80 in the samples ranged from 12 to 800 ng/g lipid, making this consistently one of the most abundant compounds among those analyzed, including polybrominated diphenyl ethers (PBDEs), hexabromocyclododecane (HBCDD), and methoxylated PBDEs. The known occurrence of 3,3‘,5,5‘-tetrabromo-2,2‘-biphenyldiol (2,2‘-diOH-BB80) in the marine environment as a natural product suggests that its methylated derivative, 2,2‘-diMeO-BB80, is also of natural origin. To obtain the necessary authentic standards, synthesis was performed of 2,2‘-diMeO-BB80 and the known natural product 2‘,6-dimethoxy-2,3‘,4,5‘-tetrabromodiphenyl ether (2‘,6-diMeO-BDE68).
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•Fifty-one studies on E/BFR metabolism have been mostly on PBDE, HBCDD and TBBPA.•More E/BFR studies on metabolism shown in e.g. fish, birds, rodents and mammals.•The metabolism and ...toxicokinetics are critically understudied for 30 E/NBFRs.•Species-specific differences in metabolic capacity of BFRs exists across species.•In vitro metabolism studies often lack, e.g. active controls, ignore enzyme activity.
Over the past few decades, production trends of the flame retardant (FR) industry, and specifically for brominated FRs (BFRs), is for the replacement of banned and regulated compounds with more highly brominated, higher molecular weight compounds including oligomeric and polymeric compounds. Chemical, biological, and environmental stability of BFRs has received some attention over the years but knowledge is currently lacking in the transformation potential and metabolism of replacement emerging or novel BFRs (E/NBFRs). For articles published since 2015, a systematic search strategy reviewed the existing literature on the direct (e.g., in vitro or in vivo) non-human BFR metabolism in fauna (animals). Of the 51 papers reviewed, and of the 75 known environmental BFRs, PBDEs were by far the most widely studied, followed by HBCDDs and TBBPA. Experimental protocols between studies showed large disparities in exposure or incubation times, age, sex, depuration periods, and of the absence of active controls used in in vitro experiments. Species selection emphasized non-standard test animals and/or field-collected animals making comparisons difficult. For in vitro studies, confounding variables were generally not taken into consideration (e.g., season and time of day of collection, pollution point-sources or human settlements). As of 2021 there remains essentially no information on the fate and metabolic pathways or kinetics for 30 of the 75 environmentally relevant E/BFRs. Regardless, there are clear species-specific and BFR-specific differences in metabolism and metabolite formation (e.g. BDE congeners and HBCDD isomers). Future in vitro and in vivo metabolism/biotransformation research on E/NBFRs is required to better understand their bioaccumulation and fate in exposed organisms. Also, studies should be conducted on well characterized lab (e.g., laboratory rodents, zebrafish) and commonly collected wildlife species used as captive models (crucian carp, Japanese quail, zebra finches and polar bears).
Persistent organic pollutants (POPs) in wildlife and humans remain a cause of global concern, both in regard to traditional POPs, such as the polychlorinated biphenyls (PCBs), and emerging POPs, such ...as the polybrominated diphenyl ethers (PBDEs). To determine the time related concentrations, we analyzed human milk for these substances at three time points between 1987 and 1999. Polychlorobiphenylols (OH-PCBs), the dominating class of PCB metabolites, some of which are known to be strongly retained in human blood, were also included in the assessment.
We obtained milk from the Faroe Islands, where the population is exposed to POPs from their traditional diet (which may include pilot whale blubber). In addition to three pools, nine individual samples from the last time point were also analyzed. After cleanup, partitioning of neutral and acidic compounds, and separation of chemical classes, the analyses were carried out by gas chromatography and/or gas chromatography/mass spectrometry.
Compared to other European populations, the human milk had high PCB concentrations, with pool concentrations of 2300 ng/g fat 1987, 1600 ng/g fat in 1994, and 1800 ng/g fat in 1999 (based on the sum of eleven major PCB congeners). The nine individual samples showed great variation in PCB concentrations. The OH-PCBs were present in trace amounts only, at levels of approximately 1% of the PCB concentrations. The PBDE concentrations showed a clear increase over time, and their concentrations in human milk from 1999 are among the highest reported so far from Europe, with results of individual samples ranging from 4.7 to 13 ng/g fat
Although remote from pollution sources, the Faroe Islands show high concentrations of POPs in human milk, particularly PCBs, but also PBDEs. The PBDEs show increasing concentrations over time. The OH-PCB metabolites are poorly transferred to human milk, which likely is related to their acidic character.
Fire incidents have decreased significantly over the last 20 years due, in part, to regulations requiring addition of flame retardants (FRs) to consumer products. Five major classes of brominated ...flame retardants (BFRs) are hexabromocyclododecane isomers (HBCDs), tetrabromobisphenol-A (TBBPA) and three commercial mixtures of penta-, octa- and deca-polybrominated diphenyl ether (PBDE) congeners, which are used extensively as commercial FR additives. Furthermore, concentrations of PBDEs have been rapidly increasing during the 1999s in human breast milk and a number of endocrine effects have been reported. We used the H295R human adrenocortical carcinoma cell line to assess possible effects of some of these BFRs (PBDEs and several of their hydroxylated (OH) and methoxylated (CH
3O) metabolites or analogues), TBBPA and brominated phenols (BPs) on the combined 17α-hydroxylase and 17,20-lyase activities of CYP17. CYP17 enzyme catalyzes an important step in sex steroidogenesis and is responsible for the biosynthesis of dehydroepiandrosterone (DHEA) and androstenedione in the adrenals. In order to study possible interactions with BFRs, a novel enzymatic method was developed. The precursor substrate of CYP17, pregnenolone, was added to control and exposed H295R cells, and enzymatic production of DHEA was measured using a radioimmunoassay. In order to avoid pregnenolone metabolism via different pathways, specific chemical inhibitor compounds were used. None of the parent/precursor BFRs had a significant effect (
P < 0.05) on CYP17 activity except for BDE-183, which showed significant inhibition of CYP17 activity at the highest concentration tested (10 μM), with no signs of cytotoxicity as measured by mitochondrial toxicity tests (MTT). A strong inhibition of CYP17 activity was found for 6-OH-2,2′,4,4′-tetrabromoDE (6-OH-BDE47) with a concentration-dependent decrease of almost 90% at 10 μM, but with a concurrent decrease in cell viability at the higher concentrations. Replacement of the 6-OH group by a 6-CH
3O group eliminated this cytotoxic effect, but CYP17 activity measured as DHEA production was still significantly inhibited. Other OH- or CH
3O-PBDE analogues were used to elucidate possible structural properties behind this CYP17 inhibition and associated cytotoxicity, but no distinct structure activity relationship could be determined.
These in vitro results indicate that OH and CH
3O-PBDEs have potential to interfere with CYP17 activity for which the in vivo relevance still has to be adequately determined.
Humans and wildlife are exposed to an intractably large number of different combinations of chemicals via food, water, air, consumer products, and other media and sources. This raises concerns about ...their impact on public and environmental health. The risk assessment of chemicals for regulatory purposes mainly relies on the assessment of individual chemicals. If exposure to multiple chemicals is considered in a legislative framework, it is usually limited to chemicals falling within this framework and co-exposure to chemicals that are covered by a different regulatory framework is often neglected. Methodologies and guidance for assessing risks from combined exposure to multiple chemicals have been developed for different regulatory sectors, however, a harmonised, consistent approach for performing mixture risk assessments and management across different regulatory sectors is lacking. At the time of this publication, several EU research projects are running, funded by the current European Research and Innovation Programme Horizon 2020 or the Seventh Framework Programme. They aim at addressing knowledge gaps and developing methodologies to better assess chemical mixtures, by generating and making available internal and external exposure data, developing models for exposure assessment, developing tools for in silico and in vitro effect assessment to be applied in a tiered framework and for grouping of chemicals, as well as developing joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern. The projects EDC-MixRisk, EuroMix, EUToxRisk, HBM4EU and SOLUTIONS have started an exchange between the consortia, European Commission Services and EU Agencies, in order to identify where new methodologies have become available and where remaining gaps need to be further addressed. This paper maps how the different projects contribute to the data needs and assessment methodologies and identifies remaining challenges to be further addressed for the assessment of chemical mixtures.
•Mapping EU funded research projects to different aspects of mixture risk assessment.•Overview of current status and methodological developments•Need to further address data and knowledge gaps overarching different chemical sectors
Background: An important question is whether human serum levels of persistent organic pollutants has continued to decrease during the last decades. The aim of this study was to assess ...intra-individual variations over time of serum levels of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153), 1,1-dichloro-2,2-bis(4-chlorophenyl)-ethene (
p,
p′-DDE) and hexachlorobenzene (HCB), considering the impact of a number of possible determinants.
Methods: Blood samples were drawn for the same 39 subjects in 1991 and 2001. Interviews were made at both occasions. Lipid adjusted serum concentrations of CB-153,
p,
p′-DDE and HCB were determined in both sets of blood samples using gas chromatography–mass spectrometry. The fatty acid composition of the serum lipids was analyzed by means of gas–liquid chromatography.
Result: The CB-153 concentrations in serum had averagely decreased with 34% in between 1991 and 2001 (
p
<
0.001). Of individual determinants only increasing BMI was associated with decreasing CB-153 levels (
β
=
−1.0, 95% CI −1.8, −0.2,
p
=
0.01), explaining 13% of the variation. The average decrease of
p,
p′-DDE was 55%, and could only weakly be associated with a relative increase of BMI (
β
=
−1.0, 95% CI −2.3, 0.2,
p
=
0.09), explaining only 5% of the variation. The average decrease of HCB was 53%, and was associated only with high fish consumption in 1991, explaining 12% of the variation.
Conclusions: The results support a continuing decrease in human body burdens of PCBs, DDE and HCB during the 1990s. The explanatory factors relative change of BMI and fish consumption explained only a minor part of the time-related variations in serum levels.
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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