Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants used in a variety of consumer products. In the past 25 years, PBDEs have become ubiquitous environmental contaminants. They have been detected in soil, air, sediments, birds, marine species, fish, house dust, and human tissues, blood and breast milk. Diet and house dust appear to be the major sources of PBDE exposure in the general population, though occupational exposure can also occur. Levels of PBDEs in human tissues are particularly high in North America, compared to Asian and European countries, and have been increasing in the past 30 years. Concentrations of PBDEs are particularly high in breast milk, resulting in high exposure of infants. In addition, for toddlers, dust has been estimated to account for a large percentage of exposure. PBDEs can also cross the placenta, as they have been detected in fetal blood and liver. Tetra-, penta- and hexaBDEs are most commonly present in human tissues. The current greatest concern for potential adverse effects of PBDEs relates to their developmental neurotoxicity. Pre- or postnatal exposure of mice or rats to various PBDEs has been shown to cause long-lasting changes in spontaneous motor activity, mostly characterized as hyperactivity or decreased habituation, and to disrupt performance in learning and memory tests. While a reduction in circulating thyroid hormone (T4) may contribute to the developmental neurotoxicity of PBDEs, direct effects on the developing brain have also been reported. Among these, PBDEs have been shown to affect signal transduction pathways and to cause oxidative stress. Levels of PBDEs causing developmental neurotoxicity in animals are not much dissimilar from levels found in highly exposed infants and toddlers.

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

Polybrominated diphenyl ethers, PBDEs, are a class of brominated flame retardants that, like other persistent organic pollutants (POPs), have been found in humans, wildlife, and biota worldwide. Unlike other POPs, however, the key routes of human exposure are not thought to be food and fish, but rather are from their use in household consumer products, and to the high levels of PBDEs found in house dust. The exposure of Americans to PBDEs was systematically evaluated in this study. First, exposure media data on PBDE congeners were compiled. Then, an adult intake dose was derived using exposure factors in combination with these data. The exposure pathways evaluated included food and water ingestion, inhalation, and ingestion and dermal contact to house dust. These intakes were converted to a body burden using a simple pharmacokinetic (PK) model. The predicted body burdens were compared with representative profiles of PBDEs in blood and milk. The adult intake dose of total PBDEs was estimated to be 7.7 ng/kg body weight/day, and children's estimated intakes were higher at 49.3 ng/kg/day for ages 1–5, 14.4 ng/kg/day for 6–11, and 9.1 ng/kg/day for 12–19. The much higher dose for the child age 1–5 was due to the doubling of dust ingestion from 50 to 100 mg/day. The predicted adult body burden of total PBDEs was 33.8 ng/kg lipid weight (lwt), compared to representative measurements in blood and milk at 64.0 and 93.7 ng/g lwt, respectively Most of this apparent underprediction in total concentration was due to an underprediction of the key congener, BDE 47. The value for BDE 47 half-life in the body was identified as the variable most likely in error in this exercise. Other congener predictions compared well with measurements, suggesting general validity with the approach. An important finding from this assessment is that the food intake estimate of about 1.3 ng/kg/day (of the 7.7 ng/kg/day total) cannot explain current US body burdens; exposures to PBDEs in house dust accounted for 82% of the overall estimated intakes.

Exposure of Americans to polybrominated diphenyl ethers.

Background/objective: Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the developing brain, we reviewed the scientific literature on these mechanisms.

Data synthesis: Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate–nitric oxide–cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability 
(via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca2+) homeostasis, and intracellular signaling pathways.

Discussion: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca2+ homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function.

Conclusions: The increased hazard for developmental neurotoxicity by hydroxylated (OH-)PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity.

Neurotoxicity of Brominated Flame Retardants: (In)direct Effects of Parent and Hydroxylated Polybrominated Diphenyl Ethers on the (Developing) Nervous System

Human health risk associated with brominated flame-retardants (BFRs).

EFSA was asked by the European Commission to deliver a scientific opinion on polybrominated diphenyl ethers (PBDEs) in food. PBDEs are additive flame retardants which are applied in plastics, textiles, electronic castings and circuitry. PBDEs are ubiquitously present in the environment and likewise in biota and in food and feed. Data from the analysis of 19 PBDE congeners in 3,971 food samples were provided to EFSA by 11 European countries. Eight congeners were considered by the Panel on Contaminants in the Food Chain (CONTAM Panel) to be of primary interest: BDE-28, -47, -99, -100, -153, -154, -183 and -209. The highest dietary exposure is to BDE-47 and -209. Toxicity studies were carried out with technical PBDE mixtures or individual congeners. Main targets were the liver, thyroid hormone homeostasis and the reproductive and nervous system. PBDEs cause DNA damage through the induction of reactive oxygen species. The Panel identified effects on neurodevelopment as the critical endpoint, and derived benchmark doses (BMDs) and their corresponding lower 95 % confidence limit for a benchmark response of 10 %, BMDL10s, for a number of PBDE congeners: BDE-47, 309 μg/kg b.w.; BDE-99, 12 μg/kg b.w.; BDE-153, 83 μg/kg b.w.; BDE-209, 1,700 μg/kg b.w. Due to the limitations and uncertainties in the current database, the Panel concluded that it was inappropriate to use these BMDLs to establish health based guidance values, and instead used a margin of exposure (MOE) approach for the health risk assessment. Since elimination characteristics of PBDE congeners in animals and humans differ considerably, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that for BDE-47, -153 and -209 current dietary exposure in the EU does not raise a health concern. For BDE-99 there is a potential health concern with respect to current dietary exposure. © European Food Safety Authority, 2011 1 On request from the European Commission, Question No EFSA-Q-2009-00684, adopted on 9 May 2011. 2 Panel members: Jan Alexander, Diane Benford, Alan Raymond Boobis, Sandra Ceccatelli, Bruce Cottrill, Jean-Pierre Cravedi, Alessandro Di Domenico, Daniel Doerge, Eugenia Dogliotti, Lutz Edler, Peter Farmer, Metka Filipic, Johanna Fink-Gremmels, Peter Furst, Thierry Guerin, Helle Katrine Knutsen, Miroslav Machala, Antonio Mutti, Martin Rose, Josef Rudolf Schlatter and Rolaf van Leeuwen. Correspondence: contam@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Brominated Flame Retardants in Food: Ake Bergman, Alan Raymond Boobis, Sandra Ceccatelli, Jean-Pierre Cravedi, Metka Filipic, Peter Furst, Niklas Johansson, Helle Knutsen, Miroslav Machala, Franco Merletti, Olaf Papke, Dieter Schrenk, Rolaf van Leeuwen, Stefan van Leeuwen and Marco Zeilmaker for the preparatory work on this scientific opinion and the hearing experts: Bas Bokkers and Catherine Viguie, and EFSA staff: Alessandro Carletti, Gina Cioacata, Luisa Ramos Bordajandi and Elena Scaravelli for the support provided to this scientific opinion. The CONTAM Panel acknowledges all the European countries that provided PBDEs occurrence data in food and supported the consumption data collection for the Comprehensive European Food Consumption Database. 4 The term “intra-species” has been replaced by “inter-species” in the Summary and in Chapter 9.1.

https://www.cancer-environnement.fr/Portals/0/Documents%20PDF/EFSA,%202011.pdf

Scientific Opinion on Polybrominated Diphenyl Ethers (PBDEs) in Food

Toxicokinetics of Polybrominated Diphenyl Ether Congeners 47, 99, 100, and 153 in Mice

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

Phototoxicity is a common safety concern encountered by project teams in pharmaceutical research and has the potential to stop progression of an otherwise promising candidate molecule. This perspective aims to provide an overview of the approaches toward mitigation of phototoxicity that medicinal chemists have taken during the lead optimization phase in the context of regulatory standards for photosafety evaluation. Various strategies are laid out based on available literature examples in order to highlight how structural modification can be utilized toward successful mitigation of a phototoxicity liability. A proposed flowchart is presented as a guidance tool to be used by the practicing medicinal chemist when facing a phototoxicity risk. The description of available tools to consider in the drug design process will include an overview of the evolution of in silico methods and their application as well as structure alerts for consideration as potential phototoxicophores.

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery.

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Toxicokinetics of Polybrominated Diphenyl Ether Congeners 47, 99, 100, and 153 in Mice

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

Phototoxicity─Medicinal Chemistry Strategies for Risk Mitigation in Drug Discovery.