Elsevier

NeuroToxicology

Volume 32, Issue 1, January 2011, Pages 9-24
NeuroToxicology

Review
Is decabromodiphenyl ether (BDE-209) a developmental neurotoxicant?

https://doi.org/10.1016/j.neuro.2010.12.010Get rights and content

Abstract

Polybrominated diphenyl ether (PBDE) flame retardants have become ubiquitous environmental pollutants. The relatively higher body burden in toddlers and children has raised concern for their potential developmental neurotoxicity, which has been suggested by animal studies, in vitro experiments, and recent human epidemiological evidence. While lower brominated PBDEs have been banned in several countries, the fully brominated decaBDE (BDE-209) is still utilized, though manufacturers will discontinue production in the U.S.A. in 2013. The recent decision by the U.S. Environmental Protection Agency to base the reference dose (RfD) for BDE-209 on a developmental neurotoxicity study has generated some controversy. Because of its bulky configuration, BDE-209 is poorly absorbed and does not easily penetrate the cell wall. Its acute and chronic toxicities are relatively low, with the liver and the thyroid as the primary targets, though there is some evidence of carcinogenicity. A few animal studies have indicated that BDE-209 may cause developmental neurotoxicity, affecting motor and cognitive domains, as seen for other PBDEs. Limited in vivo and in vitro studies have also evidenced effects of BDE-209 on thyroid hormone homeostasis and direct effects on nervous cells, again similar to what found with other lower brominated PBDEs. In contrast, a recent developmental neurotoxicity study, carried out according to international guidelines, has provided no evidence of adverse effects on neurodevelopment, and this should be considered in a future re-evaluation of BDE-209. While estimated exposure to BDE-209 in children is believed to be several orders of magnitude below the most conservative RfD proposed by the USEPA, questions remain on the extent and relevance of BDE-209 metabolism to lower brominated PBDEs in the environment and in humans.

Introduction

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants consisting of 209 congeners, which have been commercialized as penta-, octa-, and deca-brominated mixtures (Alaee et al., 2003). PentaBDE and octaBDE mixtures are no longer produced and commercialized in the European Union and the United States, though they are still used in other parts of the world. In contrast, decaBDE continues to be widely used, though some European countries (e.g. Norway) or states in the U.S.A. (e.g. Maine) have recently banned their use. The manufacturers have agreed to discontinue production of decaBDE in the U.S.A. as of 2013 (USEPA, 2010). PBDEs are additive flame retardants, i.e. they are not bound to the polymer like other flame retardants, and can leach from the products and find their way into the environment. In the past decade, PBDEs have become widespread environmental pollutants, having been detected in outdoor and indoor air, dust, sediments, soil, sludge, birds, fish, marine mammals and other mammals (deWit, 2002, Hites et al., 2004, Law et al., 2006, Chen and Hale, 2010, USEPA, 2010). Exposure of humans has also been documented by several studies (Gill et al., 2004, McDonald, 2005). Exposure occurs primarily through dust and through the diet. Body burden is higher, by at least an order of magnitude, in the U.S. population compared to Japan and the E.U. (Thomsen et al., 2002, Schecter et al., 2005a, Lorber, 2007, USEPA, 2010), though more recent data indicate high levels of exposures in fast developing nations such as India and China (J. Wang et al., 2010a). The highest body burden is found in infants and children, because of exposure through breast milk and household dust (Furst, 2006, Schecter et al., 2003, Fischer et al., 2006, Harrad et al., 2008a), and in occupationally exposed workers (Sjodin et al., 1999, Qu et al., 2007). PBDEs have also been found to cross the placenta, and levels in cord blood are comparable to those found in the mothers (Gomara et al., 2007). A recent document, the “San Antonio statement of brominated and chlorinated flame retardants”, voices concern for the widespread contamination of these compounds, including PBDEs (DiGangi et al., 2010).

Section snippets

Developmental neurotoxicity of tetra-, penta-, and hexa-BDEs

The high body burden during early development has raised concerns about possible developmental toxicity and neurotoxicity of PBDEs. Several studies have indicated that PBDEs cause developmental neurotoxicity, and recent reviews have summarized the findings of animal and in vitro studies (Branchi et al., 2003, Birnbaum and Staskal, 2004, McDonald, 2005, Costa and Giordano, 2007, Costa et al., 2008, Williams and DeSesso, 2010). In vivo exposure to various PBDEs [BDE-47, BDE-99, BDE-153, DE-71 (a

General toxicology of BDE-209

BDE-209 (3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether) is a fully brominated PBDE. It is sold as a decaBDE mixture which contains primarily (>97%) BDE-209, minor amounts of nonaBDEs (BDE-206, BDE-207, BDE-208), and traces of octaBDEs (Goodman, 2009). Among all PBDEs, BDE-209 has the most extensive toxicological database. Standard toxicology studies (e.g. acute, sub-chronic, chronic, reproductive/developmental toxicity) are available, as well as a carcinogenicity study. These studies have been

Animal studies

There are only a limited number of published studies investigating the developmental neurotoxicity of BDE-209, and a summary is given in Table 1. A first series of studies was carried out at Uppsala University in Sweden by Viberg, Eriksson, and their colleagues (Viberg et al., 2003a, Viberg et al., 2007, Viberg et al., 2008, Johansson et al., 2008, Viberg, 2009a), and these have been critically discussed in some recent publications (Goodman, 2009, Hardy et al., 2009). The same paradigm of

Occurrence and body burden of BDE-209

The analysis of BDE-209 is considered a challenging task, due to its high molecular weight, its peculiar chromatographic characteristics, its thermolability and photosensitivity, and the possibility of contamination from flame-retarded electronic equipment (Thuresson et al., 2005). Thus, it is not surprising that much less information exists on levels of BDE-209 in environmental media, biota and humans, compared to other lower-brominated PBDEs. Furthermore, the indicated issues may lead to

Derivation of an RfD for BDE-209

Over the years, various agencies and organizations have proposed reference doses (RfD) for BDE-209 (Table 5). The National Research Council of the National Academy of Sciences (NAS, 2000) based its RfD of 4.0 mg/kg/day on the chronic National Toxicology Program (NTP) study (NTP, 1986), by applying a 300× uncertainty factor (UF; 10× for interspecies differences, 10× for intraspecies differences, 3× for database deficiencies) to the NOAEL (no-observed adverse effect level) of 1120 mg/kg/day for

Conclusions and research needs

As other flame retardants, PBDEs have contributed to a significant reduction of mortality, morbidity, and property damage due to fires in the past several decades. Yet, their propensity to leach from the products and to become widespread environmental pollutants, have raised concerns in recent years (DiGangi et al., 2010). This has led to the ban of penta- and octa-BDEs in several countries, and restrictions on decaBDE (BDE-209) in others. One of the driving arguments for concern on PBDEs has

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Acknowledgment

Research by the authors has been supported in part by a grant from NIEHS (P30ES07033).

References (219)

  • J. Chen et al.

    Assessment of the neurotoxic mechanisms of decabrominated diphenyl ether (PBDE-209) in primary cultured neonatal rat hippocampal neurons includes alterations in second messenger signaling and oxidative stress

    Toxicol Lett

    (2010)
  • J. Cheng et al.

    Neurobehavioral effects, redox responses and tissue distribution in rat offspring developmental exposure to BDE-99

    Chemosphere

    (2009)
  • A. Christiansson et al.

    Polybrominated diphenyl ethers in aircraft cabins – a source of human exposure?

    Chemosphere

    (2008)
  • L. Claudio et al.

    Testing methods for developmental neurotoxicity of environmental chemicals

    Toxicol Appl Pharmacol

    (2000)
  • L.G. Costa et al.

    Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

    Neurotoxicology

    (2007)
  • A. Covaci et al.

    Optimization of the determination of polybrominated diphenyl ethers in human serum using solid-phase extraction and gas chromatography–electron capture negative ionization mass spectrometry

    J Chromatogr B

    (2005)
  • C.A. deWit

    An overview of brominated flame retardants in the environment

    Chemosphere

    (2002)
  • L.L. Driscoll et al.

    Chronic postnatal DE-71 exposure: effects on learning, attention and tyroxine levels

    Neurotoxicol Teratol

    (2009)
  • R.G. Ellis-Hutchings et al.

    Polybrominated diphenyl ether (PBDE)-induced alterations in vitamin A and thyroid hormone concentrations in the rat during lactation and early postnatal development

    Toxicol Appl Pharmacol

    (2006)
  • M. Frederiksen et al.

    Patterns and concentration levels of polybrominated diphenyl ethers (PBDEs) in placental tissue of women in Denmark

    Chemosphere

    (2009)
  • J.R. Gee et al.

    Acute postnatal exposure to brominated diphenylether 47 delays neuromotor ontogeny and alters motor activity in mice

    Neurotoxicol Teratol

    (2008)
  • B. Gevao et al.

    House dust as a source of human exposure to polybrominated diphenyl ethers in Kuwait

    Chemosphere

    (2006)
  • G. Giordano et al.

    Neurotoxicity of a polybrominated diphenyl ether mixture (DE-71) in mouse neurons and astrocytes is modulated by intracellular glutathione levels

    Toxicol Appl Pharmacol

    (2008)
  • J.E. Goodman

    Neurodevelopmental effects of decabromodiphenyl ether (BDE-209) and implications for the reference dose

    Regul Toxicol Pharmacol

    (2009)
  • H. Hakk et al.

    Metabolism and toxicokinetics and fate of brominated flame retardants—a review

    Environ Int

    (2003)
  • M.L. Hardy

    The toxicology of the three commercial polybrominated diphenyl oxide (ether) flame retardants

    Chemosphere

    (2002)
  • S. Harrad et al.

    Polybrominated diphenyl ethers in domestic indoor dust from Canada, New Zealand, United Kingdom and United States

    Environ Int

    (2008)
  • P. He et al.

    PBDE-47-induced oxidative stress, DNA damage and apoptosis in primary cultured rat hippocampal neurons

    Neurotoxicology

    (2008)
  • R.R. Holson et al.

    Statistical issues and techniques appropriate for developmental neurotoxicity testing. A report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints

    Neurotoxicol Teratol

    (2008)
  • X.Z. Hu et al.

    Apoptosis induction on human hepatoma cells HepG2 of decabrominated diphenyl ether (PBDE-209)

    Toxicol Lett

    (2007)
  • M.F. Hughes et al.

    In vitro dermal absorption of flame retardant chemicals

    Food Chem Toxicol

    (2001)
  • S. Jacobi et al.

    An oral (gavage) developmental neurotoxicity study of decabromodiphenyl oxide (DeBDPO) in rats

    Toxicol Lett

    (2009)
  • J. Jin et al.

    Polybrominated diphenyl ethers in the serum and breast milk of the resident population from production area, China

    Environ Int

    (2009)
  • S. Jin et al.

    Cytotoxicity and apoptosis induction on RTG-2 cells of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and decabrominated diphenyl ether (BDE-209)

    Toxicol In Vitro

    (2010)
  • N. Johansson et al.

    Neonatal exposure to deca-brominated diphenyl ether (BDE 209) causes dose–response changes in spontaneous behavior and cholinergic susceptibility in adult mice

    Neurotoxicology

    (2008)
  • B. Johnson-Restrepo et al.

    An assessment of sources and pathways of human exposure to polybrominated diphenyl ethers in the United States

    Chemosphere

    (2009)
  • M. Karlsson et al.

    Levels of brominated flame retardants in blood in relation to levels in household air and dust

    Environ Int

    (2007)
  • N. Abdelouahab et al.

    Thyroid disruption by low-dose BDE-47 in prenatally exposed lambs

    Neonatology

    (2009)
  • M. Ahn et al.

    Photodegradation of decabromodiphenyl ether adsorbed onto clay minerals, metal oxides, and sediment

    Environ Sci Technol

    (2006)
  • J.G. Allen et al.

    Personal exposure to polybrominated dipheyl ethers (PBDEs) in residential indoor air

    Environ Sci Technol

    (2007)
  • M. Athanasiadou et al.

    Polybrominated diphenyl ethers (PBDEs) and bioaccumulative hydroxylated PBDE metabolites in young humans from Managua, Nicaragua

    Environ Health Perspect

    (2008)
  • ATSDR (Agency for Toxic Substances and Disease Registry)

    Toxicological profile for polybrominated biphenyls and polybrominated diphenyl ethers

    (2004)
  • S.A. Batterman et al.

    Concentrations and emissions of polybrominated diphenyl ethers from U.S. houses and garages

    Environ Sci Technol

    (2009)
  • J.A. Biesemeier et al.

    Effects of dose, administration route an/or vehicle on decabromodiphenyl ether (decaBDE) concentrations in plasma of maternal, fetal and neonatal rats and in milk of maternal rats

    Drug Metab Disp

    (2010)
  • L.S. Birnbaum et al.

    Brominated flame retardants: cause for concern?

    Environ Health Perspect

    (2004)
  • E. Bruchajzer et al.

    Toxicity of penta- and decabromodiphenyl ethers after repeated administration to rats: a comparative study

    Arch Toxicol

    (2010)
  • Cai Y, Zhang W, Hu J, Sheng G, Chen D, Fu J. Characterization of maternal transfer of decabromodiphenyl ether (BDE-209)...
  • S. Chan et al.

    Thyroid hormones in the fetal central nervous system development

    Fetal Matern Med Rev

    (2003)
  • A. Christiansson et al.

    Identification and quantification of products formed via photolysis of decabromodiphenyl ether

    Environ Sci Pollut Res Int

    (2009)
  • C.G. Coburn et al.

    In vitro effects of environmentally relevant polybrominated diphenyl ether (PBDE) congeners on calcium buffering mechanisms in the rat

    Neurochem Res

    (2008)
  • Cited by (105)

    View all citing articles on Scopus
    View full text