Human Health State of the Science Report on Decabromodiphenyl Ether (decaBDE) (2024)

This page has been archived on the Web.

Health Canada

December 2012

(PDF Version - 272 KB)

• Synopsis
• Introduction
• Biomonitoring
• Health Effects Assessment
• Risk Characterization
• Summary
• References

Synopsis

Decabromodiphenyl ether (decaBDE) belongs to a group of structurally related chemicals known as the polybrominated diphenyl ethers (PBDEs). DecaBDE does not occur naturally in the environment and is not manufactured in Canada. However, decaBDE may be imported into Canada as a commercial mixture, or in consumer products, particularly electronic and electrical goods and textiles. The primary use of decaBDE in Canada is as a flame retardant in thermoplastics and polymer resins.

In 2006, two reports on PBDEs were published: Ecological Screening Assessment Report on Polybrominated Diphenyl Ethers and State of the Science Report for a Screening Health Assessment: Polybrominated Diphenyl Ethers (PBDEs). The conclusion of the ecological screening assessment report was that decaBDE, along with other assessed PBDEs (both reports considered PBDEs containing between 4 and 10 bromine atoms), met the criteria set out in paragraph 64(a) of the Canadian Environmental Protection Act, 1999 (CEPA 1999). On the basis of a recommendation by the Ministers of the Environment and Health published in the Canada Gazette, PBDEs, including decaBDE, were added to Schedule 1 of CEPA 1999.

In August 2010, Environment Canada published an ecological state of the science (SOS) report that examined new environmental data pertaining to the bioaccumulation and transformation of decaBDE. In the present report, Health Canada has examined new human health information that has become available on decaBDE since the original health assessment of PBDEs was published in 2006.

The health effects of decaBDE have been well studied. In laboratory animals, decaBDE affects early fetal/neonatal development, the liver, the thyroid and potentially the endocrine system. The available studies suggest that decaBDE does not have significant genotoxic potential, and there is limited evidence for carcinogenicity in experimental animals.

The predominant sources of exposure are breast milk for breast-fed infants, mouthing of hard plastic toys for children ages 0.5 to 4 years of age and indoor dust and food for all other age groups. Comparison of the critical effect levels in mammalian studies with the upper-bounding estimates of intake of decaBDE for the potentially most highly exposed age groups (breastfed infants and children aged 0.5–4 years) results in margins of exposure that are considered to be adequate to address uncertainties in the health effects and exposure databases. Comparison of the critical effect level for acute exposure with the upper-bounding exposure estimate for children (aged 0.5–4 years) mouthing hard plastic toys containing decaBDE also results in a margin of exposure considered to be adequate to address uncertainties in the health effects and exposure databases. Additionally, recent unpublished biomonitoring data measuring levels of decaBDE in human serum in the general population of Canada suggest that the upper-bounding estimates of daily intake are conservative. This further supports the adequacy of the margins of exposure derived in this report.

Ongoing ecological risk management initiatives in Canada are expected to result in a reduction of human exposure to decaBDE and other PBDE congeners.

State of the Science Report

October 2012

Decabromodiphenyl Ether (decaBDE)

CAS^[1] No. 1163-19-5

Top of Page

Introduction

Under the Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999), the Minister of Health may gather information and conduct investigations and evaluations, including screening assessments, relevant for the purpose of assessing whether a substance is entering or may enter the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.

Decabromodiphenyl ether (decaBDE) and other polybrominated diphenyl ethers (PBDEs) (i.e., those with four to nine bromine atoms) were nominated for inclusion in a pilot phase for preparation of screening assessments under CEPA1999. As a result, an Ecological Screening Assessment Report on Polybrominated Diphenyl Ethers (Environment Canada 2006) and a State of the Science Report for a Screening Health Assessment: Polybrominated Diphenyl Ethers (PBDEs) (Health Canada 2006) were both published in 2006 and the Ministers published their final conclusions and recommendation for adding the PBDEs to Schedule 1 of CEPA 1999 in Decembre 2006 (Canada 2006).

Environment Canada published an ecological state of the science (SOS) report for decaBDE in August 2010 (Environment Canada 2010). This SOS report includes new information on the bioaccumulation and transformation of decaBDE not considered in the original ecological screening assessment report on PBDEs. Based on the updated literature, the SOS report examines whether decaBDE meets the criteria for bioaccumulation as defined in the Persistence and Bioaccumulation Regulations under CEPA 1999 (Canada 2000) or whether the substance may transform in the environment to bioaccumulative products. It does not make a conclusion on the toxicity of decaBDE, as the substance was previously found to meet the criteria for toxicity under paragraph 64(a) of CEPA 1999. Links to all of the above-mentioned reports are available on the Environment Canada Website.

Health Canada initiated a review of the state of the science with a focus on decaBDE in order to evaluate information not considered in the original report for a screening health assessment of PBDEs.

This evaluation is considered a state of the science (SOS) review. While it does not critique all studies cited, it considers the reliability of individual studies when forming a weight of evidence for the evaluation of risk to human health. This SOS report on decaBDE was prepared by evaluators within the Existing Substances Risk Assessment Program of Health Canada and incorporates input from other programs within Health Canada. This SOS report has also undergone external written peer review and consultation. Comments on the technical portions were received from scientific experts selected and directed by Meridian Environmental Inc. and from staff of Australia’s National Industrial Chemicals Notification and Assessment Scheme for adequacy of data coverage and defensibility of the conclusions. Although external comments were taken into consideration, the final content of the SOS report remains the responsibility of Health Canada.

Information identified as of September 2011 was considered for inclusion in this SOS report. Additionally, one Canadian study published after this date and identified during public comments was added. The critical information and considerations upon which the assessment is based are summarized below.

Decabromodiphenyl ether (decaBDE) belongs to a group of structurally related chemicals known as the polybrominated diphenyl ethers (PBDEs) and is numbered according to the International Union of Pure and Applied Chemistry as the BDE-209 congener, with a corresponding structure of 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (Birnbaum and Cohen Huba 2006; La Guardia et al. 2006) (Figure 1). DecaBDE is listed on the Government of Canada’s Domestic Substances List. For additional background information on decaBDE, the reader should refer to the ecological SOS report on decaBDE published by Environment Canada in August 2010 (Environment Canada 2010).

DBDE does not occur naturally in the environment. Results of a section 71 survey under CEPA 1999 (Canada 2001) indicated that decaBDE is not manufactured in Canada. However, decaBDE may be imported into Canada either in the form of its commercial mixture, DecaBDE, or in consumer products, particularly electronic and electrical goods and textiles. The current commercial product typically contains 97–98% decaBDEalong with 0.3–3.0% other PBDEs, mainly nonabromodiphenyl ether (nonaBDE). Older commercial DecaBDE products typically contained 77.4% decaBDE, 21.8% nonaDBE and 0.8% octabromodiphenyl ether (octaBDE) (IPCS 1994). This assessment considers both decaBDE and its commercial mixture, DecaBDE.

Results of a section 71 survey under CEPA 1999 (Canada 2001) indicated that, similar to other countries, the primary uses of decaBDE in Canada are as a flame retardant in thermoplastics and polymer resins with widespread application in a variety of consumer electronic and electrical goods, such as televisions, computers, household appliances, hairdryers, cables and wires. DecaBDE is also widely used in the construction and automobile industries and is found in textiles used for furniture upholstery, carpets, curtains, etc. (Alaee et al. 2003; BSEF 2009; Ghanem and Baker 2009).

There are currently limited data on the levels of decaBDE in environmental media and food, especially Canadian-specific data. Available data upon which to base estimates of general population exposure to decaBDE are quite disparate, in that some authors reported concentrations of decaBDE (measured as the BDE-209 congener) in media, whereas others reported levels of total PBDEs without further identification of specific concentrations of BDE-209. For the purposes of this assessment, only studies that specifically report BDE-209 concentrations are considered in order to derive meaningful estimates of exposure of the general population to decaBDE.

Based on reported concentrations of decaBDE in ambient and indoor air, dust, water, various foodstuffs and human breast milk, along with standard reference values for six different age groups, including breastfed infants, upper-bounding estimates of total daily intake of decaBDE were determined to range from 0.0079 to 0.187 µg/kg-bw per day for the various age groups of the general population in Canada (Table 1). The predominant sources of exposure are breast milk for breast-fed infants and indoor dust and food for all other age groups, except children ages 0.5 to 4 years (see consumer products section). (Note: As discussed in the next section, recent unpublished biomonitoring data measuring levels of decaBDE in human serum in the general population of Canada suggest that the upper-bounding estimates of daily intake are conservative.)

As decaBDE is not manufactured in Canada, the greatest industrial contribution of decaBDE to ambient air is expected to occur during its use in the manufacture of consumer products. Facilities engaged in the recycling of computer and electronic goods are also expected to contribute to increased ambient air concentrations of decaBDE in those localized areas; overall, however, exposure of the general Canadian population to decaBDE from ambient air is considered to be low. As noted above, indoor dust and food are the predominant sources of exposure of the general Canadian population to decaBDE(Table 1). DecaBDE can be released from consumer products and become incorporated into indoor dust or adsorbed onto airborne particles, which may then be inhaled and/or ingested (Hale et al. 2002; Takigami et al. 2008). Data on the levels of decaBDE in food are limited, but recent studies have shown low concentrations of decaBDE in a number of food groups, including meat, dairy products, fish, shellfish, eggs and oils (Gomara et al. 2006; Schecter et al. 2006a; Guo et al. 2007, 2008; Akutsu et al. 2008; Knutsen et al. 2008; van Leeuwen and de Boer 2008; Covaci et al. 2009; Fernandes et al. 2009; Dirtu and Covaci 2010; J. Wang et al. 2010; Shanmuganathan et al. 2011; Ucar et al. 2011). Compared with the lower brominated PBDEs, such as pentabromodiphenyl ether (pentaBDE), however, the contribution of food to the overall exposure of the general population in Canada to decaBDE is relatively low and is similar to the contribution from the ingestion of indoor dust (Table 1). Data on the levels of decaBDE in human breast milk are available (Inoue et al. 2006; Chao et al. 2007; Gomara et al. 2007; Johnson-Restrepo et al. 2007; She et al. 2007; Wu et al. 2007; Antignac et al. 2009; Jin et al. 2009; Koh et al. 2010; Thomsen et al. 2010; Park et al. 2011; Siddique et al. 2012). Recent North American studies have shown that regional differences are evident in the concentrations of BDE-209 reported in human breast milk. Siddique et al. (2012) reported a mean and 95^th percentile of 15 and 46 ng/g lipid, respectively, of BDE-209 in breast milk. A total of 87 samples were collected from mothers in Sherbrooke, Quebec (collected in 2003-2004) and Kingston, Ontario (collected in 2008-2009). Johnson-Restrepo et al. (2007) did not detect BDE-209 in 38 samples of breast milk collected in 2004 in Massachusetts (limit of detection = 0.005 ng/g lipid; as cited in Päpke et al. 2004), whereas Wu et al. (2007) reported a maximum BDE-209 concentration of 10.9 ng/g lipid measured in breast milk obtained between April 2004 and January 2005 from women residing in the Boston, Massachusetts, area. She et al. (2007) reported a maximum BDE-209 concentration of 4.26 ng/g lipid in 40 samples of human breast milk collected in 2003 in the northwestern United States and Vancouver, British Columbia. Schecter et al. (2006b) reported a maximum concentration of 2.5 ng/g lipid in the breast milk from 11 mothers in Texas. Park et al. (2011) reported a maximum BDE-209 concentration of 55.3 ng/g lipid obtained between 2003 and 2005 from women residing in California. The principal sources of exposure to decaBDE for the 0- to 0.5-year age group included breast milk in the breastfed group but indoor dust in the non-breastfed groups (see Table 1 and discussion under “Risk Characterization”).

Top of Page

Biomonitoring

Preliminary data from two Canadian biomonitoring studies, the Organohalogens in Pooled Serum Specimens from the Canadian Health Measures Survey (CHMS) and the Chemicals, Health and Pregnancy (CHirP) study, indicate that the concentration of decaBDE reported in Canadian serum shows a lower range of concentrations reported in serum of adults and children than those reported in the USA (Lunder et al. 2010; US EPA 2010; Rawn et al. 2011; Webster et al. 2011). In the CHM Survey, decaBDE was analysed in 59 pooled serum samples from 4583 Canadians (aged 6–79 years). Concentrations ranged from below the limit of detection to 9.6 ng/g lipid, with a population-weighted geometric mean concentration of 1.1 ng/g lipid (Rawn et al. 2011). The concentration of decaBDE was highest in 6- to 11-year-olds, with a geometric mean concentration of 3.8 ng/g lipid (Rawn et al. 2011). In the CHirP study, decaBDE in maternal serum was collected at 15 weeks’ gestation from a volunteer sample of pregnant women in the Vancouver, British Columbia, area (Webster et al. 2011). BDE-209 was detected in 18.5% of analysed maternal samples with a geometric mean concentration of 2.63 ng/g lipid (Webster et al. 2011). Comparatively, in a recent study in the United States, decaBDE levels in the serum of 20 pairs of mothers and their children from 11 different US states were reported (Lunder et al. 2010). The range of decaBDE concentrations in the mothers’ serum was from below the limit of quantification to 3.2 ng/g lipid, with a mean of 1.7 ng/g lipid. The reported range in US children aged 1.5–4 years was from below the limit of quantification to 19 ng/g lipid, with a mean of 3.5 ng/g lipid (Lunder et al. 2010). Additional biomonitoring studies of PBDEs, including BDE-209, in the United States have recently been reviewed, with concentrations in serum ranging from less than 1.0 to 233 ng/g lipid (US EPA 2010).

Other recent studies worldwide have reported concentrations of BDE-209 in adult blood (Sjodin et al. 2008; Roosens et al. 2009; Zhu et al. 2009; Frederiksen et al. 2010; Johnson et al. 2010; Uemura et al. 2010; Kalantzi et al. 2011; Liu et al. 2011; Vizcaino et al. 2011), children’s blood (Pérez-Maldonado et al. 2009; Lunder et al. 2010), umbilical cord blood (Jin et al. 2009; Frederiksen et al. 2010; Wu et al. 2010; Vizcaino et al. 2011), human placental tissue (Frederiksen et al. 2009) and human sem*n (Liu et al. 2011). Alco*ck et al. (2011) reviewed the available published human serum data and noted that the frequency of positive detection within a given sampling pool was variable and often very low; these authors suggested that a combination of uneven exposure routes and analytical difficulties with the compound itself may be confounding factors in the database. However, in the event of a large sampling pool, as is the case for the recent Canadian biomonitoring data shown above, no analytical difficulties in quantifying decaBDE were noted.

One study was identified that attempted to correlate human serum concentrations of decaBDE with breast milk measures. Schecter et al. (2006b) measured concentrations in serum and milk from 11 mothers in Austin, Texas, and found high variability in the ratios of decaBDE concentrations in blood and milk, suggesting that blood levels in this small sample could not be extrapolated to milk.

Children’s toys manufactured in China, specifically hard plastic toys, were also recently identified as a potential source of exposure of young children to decaBDE (Chen et al. 2009).

The potential exposure to decaBDE from mouthing of hard plastic toys was modelled using ConsExpo version 4.1 (ConsExpo 2006) (Table 2). A maximum BDE-209 concentration of 4232µg/g in hard plastic toys and a migration rate of 0.00296 µg/cm² per minute (Chen et al. 2009) were used to model the oral intake of BDE-209 by Canadian children in the 0.5- to 4-year age group. The upper-bounding estimate of exposure from the mouthing of hard plastic toys was 1.2 × 10^-4 mg/kg body weight (kg-bw) per day (Table 2). This is twice the exposure estimate from soil (dust) for this age group (Table 1). Mouthing of hard plastic toys is estimated to be the highest source of exposure for children ages 0.5 to 4 years of age.

The confidence in the upper-bounding estimates of exposure are moderate. Confidence in the biomonitoring data is high, as the data reflect exposure from all media and are not subject to the same limitations described below for multimedia samples. Biomonitoring data do not permit exposure source or route attribution.

The reported concentrations of BDE-209 in multiple media are uncertain for a number of reasons, including different sampling methods and unique microenvironments created by the introduction of new electronic goods and/or fabrics treated with decaBDE. Allen et al.(2008a) have proposed that such factors could potentially lead to spatial or regional variations in BDE-209 concentrations. Similarly, the photolytic degradation of BDE-209 in house dust (Harrad et al. 2008b; Stapleton and Dodder 2008) is thought to contribute to variations in indoor exposures. Recently, Alco*ck et al. (2011) concluded, based on their analysis of published studies, that measurement of decaBDE can be challenging, even for relatively simple matrices, such as sediment and dust. They noted that the choice of the analytical method used was less important than the laboratory’s experience in measuring decaBDE and the awareness of those critical parameters in an assay protocol that may affect accurate determinations of decaBDE. Overall, although there are uncertainties in the upper-bounding estimates of exposure to decaBDE, the availability of biomonitoring data for decaBDE in the serum of the general Canadian population (Rawn et al. 2011; Webster et al. 2011) strengthen the exposure database. Therefore, the limitations with the data on BDE-209 concentrations in multiple media are balanced by the availability of biomonitoring data.

Lastly, it has been suggested that BDE-202, BDE-179 and BDE-184 could be markers for debrominated forms of decaBDE, and consideration of these in characterizing general population exposure could increase the precision of exposure estimates for decaBDE (Stapleton and Dodder 2008). The margins of exposure derived were considered adequate to address such potential uncertainties.

Top of Page

Health Effects Assessment

This section focuses on new studies on the human health effects of decaBDE identified since the publication of the health assessment of PBDEs (Health Canada 2006), in particular those related to development, neurotoxicity and potential endocrine and immunotoxic effects. A summary of the new health effects studies associated with decaBDE is presented in Table 3. Studies determining the effect of decaBDE on other endpoints, such as genotoxicity, carcinogenicity and reproductive toxicity, were documented in the original Health Canada (2006) report.

As shown in Table 3, decaBDE’s primary targets in laboratory animals appear to be early fetal/neonatal development, the liver, the thyroid and potentially the endocrine system. Acute oral treatment of neonatal rats and mice resulted in neurobehavioural changes in activity at adulthood, whereas oral treatment of rat and mouse dams at higher doses during pregnancy and lactation induced potential effects on the immune system of the offspring. Several studies in rodents found effects on the liver, notably increases in weight and certain enzyme activities, and also histopathological changes. A 28-day oral study in rats, enhanced to determine endocrine effects, found a dose-dependent decrease in epididymis weight and an increase in seminal vesicle weight, and the authors suggested that there was potentially an effect on steroidogenesis (Van der Ven et al. 2008a).

The lowest decaBDE dose causing non-cancer effects in an acute dosing study was 2.22 mg/kg-bw. When decaBDE was administered as a single oral dose to 3-day-old mice in a specialized neurobehavioural toxicity study, assessment at 2 and 4 months of age indicated neurobehavioural changes, including decreased spontaneous activity (locomotion, rearing and total activity; hypoactivity) during the first 20 minutes after the mice were placed in a new environment. Additionally, a comparison of activity during this first 20-minute period with activity during the period 40–60 minutes after the mice were introduced to the novel environment, demonstrated a reduced ability to habituate (i.e., the treated mice were hyperactive, compared with controls, during the latter period). These findings generally showed a dose–response relationship at 2.22 mg/kg-bw and above. A comparison between the abilities of animals treated with a single dose to habituate at 2 and 4 months indicated a poorer performance at 4 months following a single dose (2.22 mg/kg-bw and greater), suggesting a decreasing capacity to habituate with time. A lower dose utilized in the study, 1.34 mg/kg-bw, had no effects (Johansson et al. 2008). Similarly, in mouse studies that followed a similar protocol, behavioural effects were reported at 2.22 mg/kg-bw and above. In these mice, a single oral dose on postnatal day (PND) 3 and assessment at 2–6 months of age showed treatment-related changes in spontaneous behaviour, decreased activity (hypoactivity) and poorer habituation (Viberg et al. 2001a,b 2003; Viberg 2002; all previously reported in Health Canada 2006). Although the studies by Viberg (2002) and Viberg et al. (2001a,b 2003) included a lower dose of 1.34 mg/kg-bw, it was administered on PND 10, not PND 3 (with assessment at 2–6 months of age, but no effects were observed). Independently, Rice et al. (2007) reported that neurobehavioural changes (alterations in reflexes, struggling behaviour, grip strength and locomotor activity) were noted in young mice (aged 14–70 days) following previous gavage administration of 6 mg/kg-bw per day on PNDs 2–15. Similar effects (changes in locomotion, rearing, activity and habituation) were observed at 2 months of age in young rats that had been dosed on PND 3 with a single gavage dose of 6.7 mg/kg-bw (Viberg et al. 2007). In an independent follow-up study, Rice et al. (2009) reported neurobehavioural changes in 16-month-old mice (less efficient response to fixed-ratio schedule of food reinforcement, fixed-interval schedule and light–dark visual discrimination) compared with 70-day-old mice following daily administration by gavage of a dose of 20 mg/kg-bw on PNDs 2–15. There were no treatment-related differences between the two age groups at 6 mg/kg-bw day. These data suggest that aging appears to unmask behavioural effects not evident at a younger age, i.e. early decaBDE exposure appeared to impair learning behaviour in older but not younger mice. Although the exact dosing protocols utilized by Rice et al. (2007, 2009) differed from those utilized by the Viberg and Johansson studies (cited above), in both cases, a consistent finding was that developmental behavioural effects following decaBDE exposure appeared to worsen with age (consistent with a decreasing capacity to habituate with time). Based on these considerations, the dose level of 2.22 mg/kg-bw can be considered to represent the lowest-observed-adverse-effect level (LOAEL) for the acute delayed neurobehavioural toxicity of decaBDE.

Costa and Giordano (2011) reviewed the neurodevelopmental toxicity literature on decaBDE. In regards to 14 studies conducted in rats or mice (including those mentioned above), with protocols ranging from exposures during pregnancy to exposures during PNDs 2–41 (on either single or repeated days), the weight of the evidence based on their analysis of the majority of the studies indicated subtle developmental effects, particularly in pups subjected to locomotor activity or cognitive behaviour tests. In contrast, one of the studies conducted according to the Organisation for Economic Co-operation and Development (OECD) and the US Environmental Protection Agency (EPA) guidelines for developmental neurotoxicity failed to identify such effects in rat pups at doses higher than those used in the other studies. This study was available only in abstract form to Costa and Giordano (2011) when they wrote their review, but the full article has since been published by Biesemeier et al. (2011a) and is included here. In this study, Biesemeier et al. (2011a) dosed pregnant rats from gestation day 6 to lactation day 21 with DecaBDE (97.5% decaBDE plus 2.5% nonaBDE) at doses of 0–1000 mg/kg-bw per day, and neurobehavioural tests (startle response, learning and memory) were conducted on PNDs 20, 22, 60 and 62, whereas motor activity tests were conducted on PNDs 13, 17, 61, 120 and 180. The authors declared the no-observed-adverse-effect level (NOAEL) to be 1000 mg/kg-bw per day, but the numbers of pups found dead were higher in the 100 and 1000 mg/kg-bw per day groups than in the control group, and several other treatment-related effects were observed at 1000 mg/kg-bw per day (number of missing pups was increased, some of the motor activity parameters showed significant differences at 6 months in both sexes and a few of the brain morphometric analyses were significantly different at PND 21 in males and females and at PND 72 in males). Although the authors considered that these effects were within historical control values and an increased number of deaths at 100 and 1000 mg/kg-bw per day were not related to treatment, several different parameters were affected, historical control data were not provided in the supplementary data and, of particular note, significant differences in a number of motor activity parameters all occurred at the same time point (PND 180). Additionally, the authors did not provide a rationale for the increased number of missing pups at 1000 mg/kg-bw per day, and the brain morphometric effects in this study have been documented by other investigators.^[2]

Costa and Giordano (2011) reviewed mechanistic and in vitro studies related to neurodevelopmental toxicity associated with exposure to decaBDE. As shown in their review, additional studies conducted by Eriksson, Viberg, or Johansson et al., in their laboratory, showed that oral administration of decaBDE to mice on PND 3 resulted in increased synaptophysin and calcium/calmodulin-dependent protein kinase II protein levels in the brain hippocampus 7 days after exposure, whereas administration of octaBDE and nonaBDE on PND 10 resulted in the same effects 24 hours after administration. After 2 or 3 months of age, mice administered a single dose of heptabromodiphenyl ether (heptaBDE) on PND 3, octaBDE on PND 3 or 10 or nonaBDE on PND 10 showed the same alterations in spontaneous behaviour and habituation as those seen when decaBDE was administered on PND 3. The authors considered these findings as confirming their hypothesis that decaBDE exerts its developmental neurotoxicity via the accumulation of debrominated metabolites in the brain. However, further studies to determine whether any of these metabolites is responsible for the observed effects of BDE-209 [decaBDE], had not been conducted by these authors (or other researchers). While there were several publications by different authors on various effects of lower brominated PBDEs in vitro, there were few in vitro studies with decaBDE. Of those studies conducted on nerve tissue, similar cellular effects were observed with decaBDE as with other PBDEs (i.e., oxidative stress, decreased cell viability, apoptosis), but these effects were generally observed at higher concentrations (approximately 50 µM); the authors suggested that this was because decaBDE’s bulky configuration prevents it from easily entering cells (Costa and Giordano 2011).

The apparent difference in developmental neurotoxicology results between studies conducted according to regulatory guidelines and those conducted in academic settings was further explored by Alco*ck et al. (2011). Although the studies by Eriksson, Viberg or Johansson et al. (in their laboratory) have consistently reproduced results indicating alterations in behaviour, habituation and memory that persisted in adult mice and rats when they were administered a single dose of decaBDE (and other PBDE congeners) during the “brain growth spurt” period (postnatal development spanning the first 3–4 weeks of life in rodents), no other laboratory has reported studies with similar or identical protocols. Other researchers (e.g., Hardy and Stedeford 2008; Hardy et al, 2009; Goodman 2009) have noted several limitations with these studies ranging from purity of the test compound, the experimental design, the methodology used to analyze and present the data and lack of information on the motion-measuring device. As shown above, Rice et al. (2007, 2009) also conducted developmental neurotoxicity studies of decaBDE in mice, but these followed US EPA guidelines, in which the litter was used as the statistical unit, and involved repeated dosing of different strains of mice over PNDs 2–15. Although the first study (Rice et al. 2007) did not replicate a consistent depression in motor activity over time, the follow-up study (Rice et al. 2009) showed neurobehavioural deficits in mice when they were tested at an older age (16 months), and in this case, the results were similar to those of Eriksson, Viberg, or Johansson et al., in that behavioural effects of developmental decaBDE exposure appeared to worsen with age. (Note: Alco*ck et al. [2011] cited the results of Rice et al. [2007] but not the data published in Rice et al. [2009].)

Other more recent in vivo studies that may have an impact on the developmental neurotoxicity evaluation of decaBDE are summarized below. These studies were not mentioned by Alco*ck et al. (2011) or Costa and Giordano (2011) or were cited as being “in press” by Costa and Giordano (2011).

In a developmental neurotoxicity study conducted by Fujimoto et al. (2011; reviewed in Costa and Giordano 2011), the authors determined a LOAEL of 0.7–2.4 mg/kg-bw per day (10 ppm in the diet) based on liver changes (increased liver weight and liver cell hypertrophy) and kidney changes (increased cytoplasmic eosinophilia in renal proximal tubules) in rat pups; at the higher dose levels (7–23 and 66–224 mg/kg-bw per day, corresponding to 100 and 1000 ppm, respectively), decreases in the corpus callosum area and in 20,30-cyclic nucleotide 30-phosphodiesterase activity in the cingulated deep cortex in the pup brain were observed at postnatal week 11, indicating white matter hypoplasia in oligodendrocytes, whereas at 1000 ppm, levels of thyroid hormones were decreased, with hypertrophy of thyroid follicular cells.

Liang et al. (2010a) subjected adult mice to oral gavage of decaBDE for 15, 30 or 60 days at doses of 0–160 mg/kg-bw per day. Levels of malonyldialdehyde and superoxide dismutase in brain tissue were increased and decreased, respectively, at 40–160 mg/kg-bw per day, whereas acetylcholinesterase activity was decreased at 80 and 160 mg/kg-bw per day, but there were no significant changes at 0.1 mg/kg-bw per day. As the same effects were observed in mice subjected to a self-repair experiment (i.e., no self-repair), the authors concluded that these changes caused permanent effects on the nervous system and suggested that the neurotoxicity resulted through two possible mechanisms: via oxidative lipid peroxidation or affecting the production and release of neurotransmitters due to the decrease in acetylcholinesterase activity. Zhang et al. (2010) observed the same pattern of cellular response, increase of malonyldialdehyde level and decrease of superoxide dismutase level, along with a decrease in glutathione in brain tissue when mice were gavaged with a single dose of 500 mg/kg-bw, but at the single dose of 200 mg/kg-bw, only the superoxide dismutase level decreased significantly; these results suggest that high doses of decaBDE could induce oxidative stress in nervous tissue.

Pregnant rats were gavaged with decaBDE at a dose of 4.8 mg/kg-bw per day from gestation days 7 to lactation day 7 or only during lactation days 1–7. Results of this study indicated that decaBDE and/or its debrominated congeners are transferred to the offspring via in utero and lactational exposure, that tissue levels of PBDEs in the suckling rat pups were higher in the in utero plus lactational exposure group than in the lactation-only group, and that higher tissue concentrations of PBDEs appeared to occur during the early period of lactation (higher at PND 4 compared with PND 8). DecaBDE, nonaBDE and octaBDE were all identified in pup tissues (liver, kidney, brain, whole body), with nonaBDE being the most predominant “debrominated metabolite,” and the pup brain showed the most significant difference in debrominated congener levels between treated and control pups (Zhang et al. 2011). In a study conducted by Cai et al. (2011; reviewed in Costa and Giordano 2011), the oral decaBDE dose of 4.8 mg/kg-bw per day (from gestation day 7 to PND 4) resulted in 10-fold lower levels of decaBDE in fetuses and pups compared with maternal levels, and nonaBDE and octaBDE levels were increased or showed slight changes in maternal blood and placenta over time, but were lower in fetuses and neonates, suggesting that the placenta acts as a barrier to decaBDE and its metabolites.

The studies by Fujimoto et al. (2011), Zhang et al. (2011) and Cai et al. (2011) were criticized by Biesemeier et al. (2011a,b,c) on several grounds, including failing to control for litter effects, failing to correlate findings in the pup brain with indices of developmental neurotoxicity determined by regulatory guidelines and failing to characterize the composition of the test article used, which thus prevented differentiation of impurities in the test article from true metabolites identified in pup tissues. In the case of the Fujimoto et al. (2011) study, the authors had the opportunity to respond to these criticisms (Shibutani et al. 2011) by indicating that they had recalculated their data using the litter as the experimental unit and that the results did not change their original conclusions. They also noted that morphometric changes should first be discussed in relation to cellular morphology and function of the brain area measured, which was missing in Beisemeier et al.’s (2011a) developmental neurotoxicity study, in which significant morphometic changes in the pup brain were observed. Finally, they noted that because thyrotoxic effects in pups have been reported by other authors, thyroid parameters (weight, histopathology and thyroid hormone levels) should have been examined in Beisemeier et al.’s (2011a) study (see report of this study above).

An investigation into potential endocrine effects involved the administration of decaBDE to rats at 0 or 1.87–60 mg/kg-bw per day for 28 days by gavage in an emulsion vehicle that was designed to increase the bioavailability of decaBDE by approximately 3- to 4-fold compared with dietary administration. The authors did not characterize effect levels based on administered doses. Instead, a benchmark dose (BMD) approach was used to estimate the critical effect doses (CEDs) associated with 10% changes from controls for several parameters. This study did not assess neurobehavioural changes. A dose-dependent decrease in epididymis weight (CED = 4 mg/kg-bw per day) and a dose-dependent increase in seminal vesicle weight (CED = 1.5 mg/kg-bw per day) were observed, with no corresponding histopathological changes. The authors of the study suggested that the decreased epididymis weight and increased seminal vesicle weight could have reflected modulation of the sex steroid system. It is evident that these organs, which are functionally connected to each other, should show similar weight change responses if the responses were treatment related. These findings suggest that the observed changes, in opposite directions, were adaptive rather than adverse. At higher CEDs, the females showed increases in serum triiodothyronine (T₃) level and decreases in thymus and brain weights (CEDs = 58, 75 and 125 mg/kg-bw per day, respectively). Occasional slight centrilobular hypertrophy of the liver was observed in high-dose males only (no CED determined for this effect). The investigators also estimated BMDL₁₀s, the 95% lower confidence limits of the CEDs. There were no effects on appearance, behaviour, growth, or bone, sperm or immunology measures. The LOAEL in this study is considered to be 60 mg/kg-bw per day, based on slight centrilobular hypertrophy in the liver of males observed at this dose and evidence for decreasing thymus and brain weights in females (estimated CEDs of 75 and 125 mg/kg-bw per day, respectively) (Van der Ven et al. 2008a). The experimental methods and benchmark dose modeling of this study have been debated (Hardy et al 2008 and Van der Ven et al 2008b)

Some evidence of weak immunomodulatory effects has been reported in the offspring of female rats and mice fed diets supplying decaBDE from gestation day 10 until weaning. In one rat study, a maternal dose level of about 5 mg/kg-bw per day or above resulted in B-cell activation and a reduced number of natural killer (NK) cells in the offspring (Teshima et al. 2008). In another study, 2-week-old offspring from female rats fed decaBDE at 300 mg/kg-bw per day during pregnancy through to weaning of pups (no further details provided) showed differences in splenic structure and decreases in CD19 percentage and serum interferon-y level compared with controls; the serum level of decaBDE was more than 10 times higher in the treated group offspring than in control offspring (502 vs. 46 ng/g lipid weight), whereas total metabolite concentrations were almost 3 times higher in the treated offspring (138 vs. 48 ng/g lipid weight); of the metabolite measures, heptaBDE had the greatest difference, with its levels being more than 4 times higher (93 vs. 22 ng/g lipid weight) than in control offspring (Zhou et al. 2010). In a mouse study, a significant increase in gene expression of cytokine RANTES (regulated upon activation, normal T-cell expressed, and presumably secreted) in the offspring was associated with a maternal dose level of 13 mg/kg-bw per day; there was some evidence of other effects, but these reached statistical significance only at a 10-fold higher dose level (130 mg/kg-bw per day) (Watanabe et al. 2008).^[3] In contrast, mouse pups dosed on PNDs 10–21 with a suprapharmacological dose of decaBDE (greater than the OECDlimit dose), 3300 mg/kg-bw per day, showed a disorder of the primary immune response in bronchoalveolar lavage fluid (assessed on PND 28), which suggested that cytokine production was affected at this high dose (Watanabe et al. 2010).

Several recently published studies have provided information to better characterize the absorption, distribution, metabolism and excretion of decaBDE in mammals (Hakk and Letcher 2003; Mörck et al. 2003; Sandholm et al. 2003; Huwe and Smith 2007a,b; Kierkegaard et al. 2007). The percentage of an administered dose absorbed across the gastrointestinal tract in rats ranged from approximately 7% to 26%, but one of the most extensive studies that provided key information showed that approximately 90% of the oral dose was excreted via the feces and 9% remained in the body as parent compound and metabolites (US EPA 2008; Environment Canada 2010). The metabolism of decaBDE in orally dosed mammals is summarized as follows:

• Reductive debromination to nona-, octa- and heptaBDEs is the likely first step in the metabolism of decaBDE in rats. However, in mice, the major metabolites identified in the liver, spleen and kidney were hepta-, hexa-, penta- and tetraBDEs (Liang et al. 2010b).
• The debrominated neutral metabolites then appear to undergo hydroxylation to form phenols or catechols, potentially via an arene oxide.
• The catechols may then be methylated, potentially by the action of catechol-O-methyltransferase, to form the observed guaicols.
• The guiacol metabolites could further oxidize to quinones, which are highly reactive and would bind to cellular macromolecules.
• The reactive intermediates would also be subject to rapid conjugation via Phase II metabolic processes, leading to water-soluble metabolites, which would be excreted via bile and feces, as was observed in conventional and cannulated rats.^[4]

Studies by Huwe and Smith (2007a,b) appear to indicate that the neutral debrominated metabolites make up a very small fraction (~1%) of the total PBDE mass balance in rats exposed to decaBDE. This suggests that the hydroxylation and methylation pathways and resulting metabolites are highly significant in the metabolism of decaBDE (Environment Canada 2010).

The metabolites octaBDE and nonaBDE were found in the liver and kidney of male rats fed decaBDE at 100 mg/kg-bw per day for 3 months (F. Wang et al. 2010).^[5] Also, although the molecular forms were not identified, decaBDE residues (bromine-81 isotope) were detected in liver, adrenal cortex and corpora lutea of ovaries in female rats dosed with decaBDE at 2 mg/kg-bw per day for 4 days (Seyer et al. 2010).

It is noted that this model for the metabolism of decaBDE is based mainly on studies in rats and that a model for human metabolism has not been established (US EPA 2008). In addition to the excretion routes identified in rodents, decaBDE may also be excreted to a limited extent in human breast milk. Park et al. (2011) reported the transfer of decaBDE to breast milk in the few samples with high decaBDE concentrations in California women, with heptaBDE or tetraBDE as the second major congener detected in the samples (see also description of Park et al. [2011] under “Exposure Assessment”).

Confidence in the oral health effects database for the health effects associated with decaBDE is considered to be moderate overall. The database is considered sufficient to characterize the likely most sensitive effects associated with general population exposure to decaBDE. However, there is limited information on effects via the inhalation and dermal routes of exposure.

Although the metabolism and toxico*kinetics of decaBDE have been extensively studied in rodents, due to insufficient data on toxico*kinetics in humans, a model for human metabolism has not been established. This may be important in relation to the reported neurotoxic effects of decaBDE.

Top of Page

Risk Characterization

The critical effect level for oral exposure considered most appropriate for risk characterization is the LOAEL of 2.22 mg/kg-bw (based on neurodevelopmental effects from exposure during the early days of life resulting in impaired learning behaviour in response to neurobehavioural tests in aging mice), based on several studies of different durations with appropriate endpoints. The dose level of 2.22 mg/kg bw/day was also chosen as the critical effect level for decaBDE in Health Canada (2006) based on similar development behavioural findings reported at this dose and above in other mouse studies that followed similar protocols.

As documented previously, these critical effect levels are also considered protective with regard to the increases in the incidence of benign liver tumours observed in rats chronically exposed at much higher (approximately 500-fold) oral doses of decaBDE, particularly in view of the fact that the available data for decaBDE (and PBDEs as a group) suggest that decaBDE does not have significant genotoxic potential (Health Canada 2004, 2006).

Further information supporting the choice of these LOAELs is presented below.

The US EPA used the LOAEL of 2.22 mg/kg-bw as the basis for setting a revised oral reference dose (RfD) for decaBDE (US EPA 2008), based on the same studies conducted by Eriksson, Viberg or Johansson et al. mentioned in the Health Effects section above. The final review of decaBDE by the US EPA (2008) addressed external peer review comments that has noted limitations in US EPA’s endpoint selection. The US EPA noted that most reviewers agreed with using the studies conducted by Eriksson, Viberg or Johansson et al. as a basis for setting the RfD and that the neurodevelopmental findings from these studies were also supported by an expanding body of published studies from other authors demonstrating changes in motor and cognitive activities in rodents following administration of single or repeated doses of decaBDE and other PBDE congeners.

Since the 2008 US EPA final review of decaBDE, the data and the US EPA conclusions have been challenged and other critical effect levels have been proposed (Hardy et al. (2009), Goodman (2009), Williams and DeSesso (2010), TERA (2011)). However, recent published studies support the merit of the 2.22 mg/kg-bw level as a critical effect level for risk characterization. For example, in the follow-up study by Rice et al. (2009), results similar to those published by Eriksson, Viberg or Johansson et al. were observed, demonstrating that behavioural effects of developmental decaBDE exposure worsen with age (i.e. a decreased capacity to habituate to new environments or impaired learning behaviour in response to neurobehavioural tests). In a recent study by Fujimoto et al. (2011), the authors determined a LOAEL of 0.7–2.4 mg/kg-bw per day, based on liver and kidney changes in rat pups; at the higher dose levels (7–23 and 66–224 mg/kg-bw per day), evidence for brain white matter (oligodendrocytes) hypoplasia was observed. Similarly, Liang et al. (2010a) showed evidence of permanent nervous system effects in the brains of adult mice subjected to daily doses of decaBDE, whereas studies by Cai et al. (2011) and Zhang et al. (2011) provided evidence for transfer of decaBDE and/or its metabolites to pups both in utero and by breast milk feeding when dams were dosed with 5 mg/kg-bw per day, with increased concentrations observed in pups during the early lactation phase (i.e., when the primary source of nutrition is breast milk). Such studies provide corroborative evidence supporting treatment-related neurobehavioural effects observed in mice pups dosed on PND 3 with decaBDE (or heptaBDE or octaBDE, as well as octaBDE or nonaBDE dosed on PND 10). The ongoing debate in the scientific community on these studies is acknowledged (Biesemeier et al. 2011b,c; Shibutani et al. 2011).

Thus, the weight of evidence supporting the selection of 2.22 mg/kg-bw per day as a critical effect level is supported by reviews of other international jurisdictions (i.e., US EPA) and recently published data.

As shown in the “Exposure Assessment” section, published concentrations of decaBDE in breast milk from Canadian women (She et al. 2007; Siddique et al. 2012), were utilized in determining the upper-bounding estimate of daily intake from all sources of exposure for populations in Canada. These were very similar to the breast milk concentrations reported in the USA (Schecter et al. 2006b; Johnson-Restrepo et al. 2007; Wu et al. 2007; Park et al. 2011). Also, note that unpublished data from two Canadian biomonitoring studies (Rawn et al. 2011; Webster et al. 2011) indicate a lower range of concentrations reported in serum of Canadian adults and children than those reported in the USA (Lunder et al. 2010; US EPA 2010). Therefore, these preliminary Canadian biomonitoring data indicate that the upper-bounding estimates of daily decaBDEintake for Canadian populations are conservative.

Comparison of the critical effect level (2.22 mg/kg-bw per day) with the upper-bounding estimate of intake of decaBDE for the potentially most highly exposed age group (0.05–0.187 µg/kg-bw per day in breastfed infants) results in a range of margins of exposure of approximately 11 900–44 400. Comparison of the critical effect level for acute exposure (2.22 mg/kg-bw) with the exposure estimate (1.2 × 10^-4 mg/kg-bw) for children aged 0.5–4 years mouthing hard plastic toys results in a margin of exposure of 18500. These margins of exposure are considered adequate to address uncertainties in the health effects and exposure databases.

Top of Page

Summary

In light of the limited data on the levels of decaBDE in environmental media and food, especially Canadian-specific data, and which include some information on the toxico*kinetics of decaBDE in humans and experimental animals and the endpoint chosen for the critical effect (developmental neurobehaviour), the absence of significant potential for genotoxicity and limited carcinogenicity potential in experimental animals, it is considered that the estimated margins of exposure for decaBDE, as shown in the “Risk Characterization” section, are considered to be adequate to address uncertainties in the health effects and exposure databases. There is high confidence in these estimates of exposure, because the unpublished biomonitoring data of serum decaBDE levels in the general population of Canada, suggest that the upper-bounding estimates of daily intake in this report are conservative.

DecaBDE belongs to the group of PBDEs previously addressed by Health Canada (2006). In that review, Health Canada considered exposures to total PBDEs and derived a margin of exposure of approximately 300, based on comparison of the critical effect level (i.e., 0.8 mg/kg-bw per day) with the upper-bounding deterministic estimate of exposure for the intake of total PBDEs for the potentially most highly exposed age group (2.6 µg/kg-bw per day in breastfed infants). In comparison, the current review specifically for decaDBE demonstrates a significantly greater margin of exposure for breastfed infants, a susceptible subpopulation.

In 2006, PBDEs and its congeners, including decaBDE, were added to the List of Toxic Substances in Schedule 1 of CEPA 1999 on the basis of environmental considerations (Canada 2006). As a result of these environmental considerations, the Government of Canada (Canada 2008) implemented regulations that prohibit the manufacture, use, sale, offer for sale and import of tetraBDE, pentaBDE and hexaBDE congeners and mixtures, polymers and resins containing these substances. The manufacture of heptaBDE, octaBDE, nonaBDE and decaBDE congeners is also prohibited under these Regulations, and additional regulatory actions are under development. Continuing ecological risk management initiatives in Canada are expected to result in further reduction of human exposure to decaBDE and other PBDE congeners and corresponding increase in margins of exposure.

Top of Page

References

Akutsu K, Takatori S, Nakazawa H, Hayakawa K, Izumi S, Makino T. 2008. Dietary intake estimations of polybrominated diphenyl ethers (PBDEs) based on a total diet study in Osaka, Japan. Food Addit Contam B 1:58–68.

Alaee M, Arias P, Sjodin A, Bergman A. 2003. An overview of commercially used brominated flame retardants, their applications, their use patterns in different countries/regions and possible modes of release. Environ Int 29:683–689.

Alco*ck RE, MacGillivray BH, Busby JS. 2011. Understanding the mismatch between the demands of risk assessment and practice of scientists--the case of Deca-BDE. Environ Int 37:216–225.

Allen JG, McClean MD, Stapleton HM, Webster TF. 2008a. Critical factors in assessing exposure to PBDEs via house dust. Environ Int 34:1085–1091.

Allen JG, McClean MD, Stapleton HM, Webster TF. 2008b. Linking PBDEs in house dust to consumer products using X-ray fluorescence. Environ Sci Technol 42:4222–4228.

Antignac JP, Cariou R, Zalko D, Berrebi A, Cravedi JP, Maume D, Marchand P, Monteau F, Riu A, Andre F, Le Bizec B. 2009. Exposure assessment of French women and their newborn to brominated flame retardants: determination of tri- to deca- polybromodiphenylethers (PBDE) in maternal adipose tissue, serum, breast milk and cord serum. Environ Pollut 157:164–173.

Banasik M, Hardy M, Muro-Cacho C, Hover CG, Stedeford T. 2010. Developmental immunotoxicity and the importance of controlling for litter effects [letter to the editor]. Environ Toxicol Pharmacol 29:1–2.

Banasik M, Harbison RD, Lee RV, Lassiter S, Smith CJ, Stedeford T. 2011. Comment on “Comparative tissue distribution, biotransformation and associated biological effects by decabromodiphenyl ethane and decabrominated diphenyl ether in male rats after a 90-day oral exposure study.” Environ Sci Technol 45(11):5060–5061.

Batterman SA, Chernyak S, Jia C, Godwin C, Charles S. 2009. Concentrations and emissions of polybrominated diphenyl ethers from U.S. houses and garages. Environ Sci Technol 43:2693–2700.

Batterman S, Godwin C, Chernyak S, Jia C, Charles S. 2010. Brominated flame retardants in offices in Michigan, U.S.A. Environ Int 36:548–556.

Biesemeier JA, Beck MJ, Silberberg H, Myers NR, Ariano JM, Radovsky A, Freshwater L, Sved DW, Jacobi S, Stump DG, Hardy ML, Stedeford T. 2011a. An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats. Birth Defects Res B 92:17–35.

Biesemeier JA, Ariano JM, Banasik M, Smith CJ, Senegal TW, Stedeford T. 2011b. Sample characterization: a priori to evaluating absorption, distribution, and metabolism. Toxicology 287:160–161.

Biesemeier JA, Banasik M, Zhu Y, Harbison RD, Smith CJ. 2011c. Comment on “Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation.” Reprod Toxicol 32(3):372–374.

Birnbaum LS, Cohen Huba EA. 2006. Polybrominated diphenyl ethers: a case study for using biomonitoring data to address risk assessment questions. Environ Health Perspect 114:1770–1775.

Bremmer HJ, van Veen MP. 2002. Children’s toys fact sheet: To assess the risks for the consumer. Updated version for ConsExpo 4 [Internet]. Bilthoven (NL): Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health and the Environment). RIVM Report No.: 612810012/2002.

[BSEF] Bromine Science and Environmental Forum. 2009. Brominated flame retardant Deca-BDE factsheet, January 2009. Washington (DC): BSEF.

Butt CM, Diamond ML, Truong J, Ikonomou MG, Ter Schure AFH. 2004. Spatial distribution of polybrominated diphenyl ethers in southern Ontario as measured in indoor and outdoor window organic films. Environ Sci Technol 38:724–731.

Cai Y, Zhang W, Hu J, Sheng G, Chen D, Fu J. 2011. Characterization of maternal transfer of decabromodiphenyl ether (BDE-209) administered to pregnant Sprague-Dawley rats. Reprod Toxicol 31:106–110.

Canada. 1999. Canadian Environmental Protection Act, 1999. S.C., 1999, c. 33. Canada Gazette, Part III: Vol. 22, No. 3.

Canada. 2000. Canadian Environmental Protection Act, 1999: Persistence and Bioaccumulation Regulations. P.C. 2000-348, 23 March 2000, SOR/2000-107. Canada Gazette, Part II: Vol. 134, No. 7.

Canada, Dept. of the Environment. 2001. Canadian Environmental Protection Act, 1999: Notice with respect to certain substances on the Domestic Substances List (DSL). Canada Gazette, Part I: Vol. 135, No. 46.

Canada. 2006. Order adding toxic substances to Schedule 1 to the Canadian Environmental Protection Act, 1999. 27 December 2006, SOR/2006-333. Canada Gazette, Part II: Vol. 140, No. 26.

Canada. 2008. Canadian Environmental Protection Act, 1999: Polybrominated Diphenyl Ethers Regulations. 19 June 2008, SOR/2008-218. Canada Gazette, Part II: Vol. 142, No. 14.

Chang FH, Yang CR, Tsai CY, Lin WC. 2009. Airborne polybrominated diphenyl ethers in a computer classroom of college in Taiwan. Iran J Environ Health Sci Eng 6:121–130.

Chao HR, Wang SL, Lee WJ, Wang YF, Päpke O. 2007. Levels of polybrominated diphenyl ethers (PBDEs) in breast milk from central Taiwan and their relation to infant birth outcome and maternal menstruation effects. Environ Int 33:239–245.

Chen SJ, Ma YJ, Wang J, Chen D, Luo XJ, Mai BX. 2009. Brominated flame retardants in children’s toys: concentration, composition, and children’s exposure and risk assessment. Environ Sci Technol 43:4200–4206.

[ConsExpo] Consumer Exposure Model [Internet]. 2006. Version 4.1. Bilthoven (NL): Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health and the Environment).

Costa LG, Giordano G. 2011. Is decabromodiphenyl ether (BDE-209) a developmental neurotoxicant? Neurotoxicology 32:9–24.

Covaci A, Roosens L, Dirtu AC, Waegeneers N, Van Overmeire I, Neels H, Goeyens L. 2009. Brominated flame retardants in Belgian home-produced eggs: levels and contamination sources. Sci Total Environ 407:4387–4396.

Cressey MA, Reeve EA, Rice DC, Markowski VP. 2006. Behavioral impairments produced by developmental exposure to the flame retardant decaBDE. Neurotoxicol Teratol 28:707–708 [abstract].

D’Hollander W, Roosens L, Covaci A, Cornelis C, Reynders H, Van Campenhout K, de Voogt P, Bervoets L. 2010. Brominated flame retardants and perfluorinated compounds in indoor dust from homes and offices in Flanders, Belgium. Chemosphere 81:478–487.

Dirtu AC, Covaci A. 2010. Estimation of daily intake of organohalogenated contaminants from food consumption and indoor dust ingestion in Romania. Environ Sci Technol 44:6297–6304.

Environment Canada. 2006. Ecological Screening Assessment Report on Polybrominated Diphenyl Ethers (PBDEs). June 2006.

Environment Canada. 2010. Ecological State of the Science Report on Decabromodiphenyl Ether (decaBDE): bioaccumulation and transformation. August 2010. 147 p.

Fernandes AR, Tlustos C, Smith F, Carr M, Petch R, Rose M. 2009. Polybrominated diphenylethers (PBDEs) and brominated dioxins (PBDD/Fs) in Irish food of animal origin. Food Addit Contam B 2:86–94.

Frederiksen M, Thomsen M, Vorkamp K, Knudsen LE. 2009. Patterns and concentration levels of polybrominated diphenyl ethers (PBDEs) in placental tissue of women in Denmark. Chemosphere 76:1464–1469.

Frederiksen M, Thomsen C, Froshaug M, Vorkamp K, Thomsen M, Becher G, Knudsen LE. 2010. Polybrominated diphenyl ethers in paired samples of maternal and umbilical cord blood plasma and associations with house dust in a Danish cohort. Int J Hyg Environ Health 312:233–242.

Fromme H, Korner W, Shahin N, Wanner A, Albrecht M, Boehmer S, Parlar H, Mayer R, Liebl B, Bolte G. 2009. Human exposure to polybrominated diphenyl ethers (PBDE), as evidenced by data from a duplicated diet study, indoor air, house dust, and biomonitoring in Germany. Environ Int 35:1125–1135.

Fujimoto H, Woo GH, Inoue K, Takahashi M, Hirose M, Nishikawa A,, Shibutani M. 2011. Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation. Reprod Toxicol. 31: 86-94.

Ghanem R, Baker H. 2009. Determination of decabromodiphenyl ether in backcoated textile preparation. J Hazard Mater 162:249–253.

Gomara B, Herrero L, Gonzalez MJ. 2006. Survey of polybrominated diphenyl ether levels in Spanish commercial foodstuffs. Environ Sci Technol 40:7541–7547.

Gomara B, Herrero L, Ramos JJ, Mateo JR, Fernandez MA, Garcia JF, Gonzalez MJ. 2007. Distribution of polybrominated diphenyl ethers in human umbilical cord serum, paternal serum, maternal serum, placentas, and breast milk from Madrid population, Spain. Environ Sci Technol 41:6961–6968.

Goodman JE. 2009. Neurodevelopmental effects of decabromodiphenyl ether (BDE-209) and implications for the reference dose. Regul Toxicol Pharmacol 54:91–104.

Gouin T, Thomas GO, Chaemfa C, Harner T, Mackay D, Jones KC. 2006. Concentrations of decabromodiphenyl ether in air from southern Ontario: implications for particle-bound transport. Chemosphere 64:256–261.

Guo JY, Wu FC, Mai BX, Luo XJ, Zeng EY. 2007. Polybrominated diphenyl ethers in seafood products of South China. J Agric Food Chem 55:9152–9158.

Guo JY, Meng XZ, Tang HL, Mai BX, Zeng EY. 2008. Distribution of polybrominated diphenyl ethers in fish tissues from the Pearl River Delta, China: levels, compositions, and potential sources. Environ Toxicol Chem 27:576–582.

Hakk H, Letcher RJ. 2003. Metabolism in the toxico*kinetics and fate of brominated flame retardants--a review. Environ Int 29:801–828.

Hale RC, La Guardia MJ, Harvey E, Mainor TM. 2002. Potential role of fire retardant–treated polyurethane foam as a source of brominated diphenyl ethers to the US environment. Chemosphere 46:729–735.

Hardy M, Stedeford T. 2008. Developmental neurotoxicity: when research succeeds through inappropriate statistics. Neurotoxicology 29:476.

Hardy M, Ranken P, Hsu C-H, Stedeford T. 2008. Letter to the Editor: van der Ven et al. (2008): Deriving risks based on model parameters rather than on experimental data. Toxicol Lett 182: 127-129.

Hardy ML, Banasik M, Stedeford T. 2009. Toxicology and human health assessment of decabromodiphenyl ether. Crit Rev Toxicol 39(Suppl. 3):1–44.

Harrad S, Ibarra C, Diamond M, Melymuk L, Robson M, Douwes J, Roosens L, Dirtu AC, Covaci A. 2008a. Polybrominated diphenyl ethers in domestic indoor dust from Canada, New Zealand, United Kingdom and United States. Environ Int 34:232–238.

Harrad S, Ibarra C, Abdallah MAE, Boon R, Neels H, Covaci A. 2008b. Concentrations of brominated flame retardants from the United Kingdom cars, homes, and offices: causes of variability and implications for human exposure. Environ Int 34:1170–1175.

Harrad S, Goosey E, Desborough J, Abdallah MA-E, Roosens L, Covaci A. 2010. Dust from U.K. primary school classrooms and daycare centers: the significance of dust as a pathway of exposure of young U.K. children to brominated flame retardants and polychlorinated biphenyls. Environ Sci Technol 44:4198–4202.

Health Canada. 1998. Exposure factors for assessing total daily intake of priority substances by the general population of Canada. Unpublished report. Ottawa (ON): Health Canada, Environmental Health Directorate. Available upon request.

Health Canada. 2004. Canadian Environmental Protection Act, 1999. Screening health assessment. Supporting working document. Polybrominated diphenyl ethers. Ottawa (ON): Health Canada.

Health Canada. 2006. State of the Science Report for Polybrominated Diphenyl Ethers (PBDEs) [Tetra-, penta-, hexa-, hepta-, octa-, nona- and deca- congeners] [CAS Nos. 40088-47-9, 32534-81-9, 36483-60-0, 68928-80-3, 32536-52-0, 63936-56-1, 1163-19-5]. Ottawa (ON): Health Canada.

Hoh E, Hites RA. 2005. Brominated flame retardants in the atmosphere of the east-central United States. Environ Sci Technol 39:7794–7802.

Hsu PC, Tseng LH, Lee CW. 2006. Effects of prenatal exposure of decabrominated diphenyl ether (PBDE 209) on reproductive system in male mice. Organohalogen Compd 68:1547–1550.

Huang Y-M, Chen L-G, Xu Z-C, Peng X-C, Wen L-J, Zhang S-K, Zeng M, Ye Z-X. 2010. Preliminary study of PBDE levels in house dust and human exposure to PBDEs via dust ingestion. Environ Sci [Huanjing Kexue] 31:168–172.

Huwe JK, Smith DJ. 2007a. Accumulation, whole-body depletion and debromination of decabromodiphenyl ether in male Sprague-Dawley rats following dietary exposure. Environ Sci Technol 41(7):2371–2377.

Huwe JK, Smith DJ. 2007b. Accumulation, whole-body depletion and debromination of decabromodiphenyl ether in male Sprague-Dawley rats following dietary exposure. Additions and corrections. Environ Sci Technol 41(12):4486.

Inoue K, Harada K, Takenaka K, Uehara S, Kono M, Shimizu T, Takasuga T, Senthilkumar K, Yamash*ta F, Koizumi A. 2006. Levels and concentration ratios of polychlorinated biphenyls and polybrominated diphenyl ethers in serum and breast milk in Japanese mothers. Environ Health Perspect 114:1179–1185.

[IPCS] International Programme on Chemical Safety. 1994. Brominated diphenyl ethers. Geneva (CH): World Health Organization (Environmental Health Criteria 162).

Ismail N, Gewurtz SB, Pleskach K, Whittle DM, Helm PA, Marvin CH, Tomy GT. 2009. Brominated and chlorinated flame retardants in Lake Ontario, Canada, lake trout (Salvelinus namaycush) between 1979 and 2004 and possible influences of food-web changes. Environ Toxicol Chem 28:910–920.

Jiang HP, Yu YH, Chen DJ, Wu Y, Xu B. 2008. Effect of maternal BDE-209 exposure on the expression of GAP-43 and BDNF in the hippocampus of the offspring rats. J South Med Univ [Nan Fang Yi Ke Da Xue Xue Bao] 28:1319–1322 [in Chinese; cited from Toxline abstract].

Jin J, Wang Y, Yang C, Hu J, Liu W, Cui J, Tang X. 2009. Polybrominated diphenyl ethers in the serum and breast milk of the resident population from production area, China. Environ Int 35:1048–1052.

Johansson N, Viberg H, Fredriksson A, Eriksson P. 2008. Neonatal exposure to deca-brominated diphenyl ether (PBDE 209) causes dose–response changes in spontaneous behaviour and cholinergic susceptibility in adult mice. Neurotoxicology 29:911–919.

Johnson PI, Stapleton HM, Sjodin A, Meeker JD. 2010. Relationships between polybrominated diphenyl ether concentrations in house dust and serum. Environ Sci Technol 44:5627–5632.

Johnson-Restrepo B, Addink R, Wong C, Arcaro K, Kannan K. 2007. Polybrominated diphenyl ethers and organochlorine pesticides in human breast milk from Massachusetts, USA. J Environ Monit 9:1205–1212.

Kalantzi OI, Geens T, Covaci A, Siskos PA. 2011. Distribution of polybrominated diphenyl ethers (PBDEs) and other persistent organic pollutants in human serum from Greece. Environ Int 37:349–353.

Kang Y, Wang HS, Cheung KC, Wong MH. 2011. Polybrominated diphenyl ethers (PBDEs) in indoor dust and human hair. Atmos Environ 45:2386–2393.

Kierkegaard A, Asplund L, de Wit C, McLachlan MS, Thomas GO, Sweetman AJ, Jones KC. 2007. Fate of higher brominated PBDEs in lactating cows. Environ Sci Technol 41(2):417–423.

Kim TH, Lee YJ, Lee E, Kim MS, Kwack SJ, Kim KB, Chung KK, Kang TS, Han SY, Lee J, Lee BM, Kim HS. 2009. Effects of gestational exposure to decabromodiphenyl ether on reproductive parameters, thyroid hormone levels, and neuronal development in Sprague Dawley rats offspring. J Toxicol Environ Health A 72: 1296–1303.

Knutsen HK, Kvalem HE, Thomsen C, Froshaug M, Haugen M, Becher G, Alexander J, Meltzer HM. 2008. Dietary exposure to brominated flame retardants correlates with male blood levels in a selected group of Norwegians with a wide range of seafood consumption. Mol Nutr Food Res 52:217–227.

Koh T-W, Chen SC-C, Chang-Chien G-P, Lin D-Y, Chen F-A, Chao H-R. 2010. Brest-milk levels of polybrominated diphenyl ether flame retardants in relation to women’s age and pre-pregnant body mass index. Int J Hyg Environ Health 213:59–65.

La Guardia MJ, Hale RC, Harvey E. 2006. Detailed polybrominated diphenyl ether (PBDE) congener composition of the widely used penta-, octa-, and deca-PBDE technical flame-retardant mixtures. Environ Sci Technol 40:6247–6254.

Liang S, Gao H, Zhao Y, Ma X, Sun H. 2010a. Effects of repeated exposure to decabrominated diphenyl ether (BDE-209) on mice nervous system and its self repair. Environ Toxicol Pharmacol 29:297–301.

Liang S, Li L, Zhang G. et al. 2010b. Accumulation and debromination of decabromodiphenyl ether in mice. J Environ Health 27(4):314–317 [In Chinese with English abstract].

Liu P-Y, Zhao Y-X, Zhu Y-Y, Qin Z-F, Ruan X-L, Zhang Y-C, Chen B-J, Li Y, Yan S-S, Qin X-F, Fu S, Xu X-B. 2011. Determination of polybrominated diphenyl ethers in human sem*n. Environ Int [Epub ahead of print].

Lunder S, Hovander L, Athanassiadis I, Bergman A. 2010. Significantly higher polybrominated diphenyl ether levels in young U.S. children than in their mothers. Environ Sci Technol 44:5256–5262.

Mörck A, Hakk H, örn U, Klasson-Wehler E. 2003. Decabromodiphenyl ether in the rat: absorption, distribution, metabolism, and excretion. Drug Metab Dispos 31(7):900–907.

[NICNAS] National Industrial Chemicals Notification and Assessment Scheme. 2001. Priority Existing Chemical Assessment Reports - PEC No. 20 - Polybrominated Flame Retardants. Australian Government, Department of Health and Ageing.

Norris B, Smith S. 2002. Research into the mouthing behaviour of children up to 5 years old. Report commissioned by Consumer and Competition Policy Directorate, Department of Trade and Industry, London, UK.

Päpke O, Fürst P, Herrmann T. 2004. Determination of polybrominated diphenylethers (PBDEs) in biological tissues with special emphasis on QC/QA measures. Talanta 63: 1203-1211.

Park JS, She J, Holden A, Sharp M, Gephart R, Souders-Mason G, Zhang V, Chow J, Leslie B, Hooper K. 2011. High postnatal exposures to polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) via breast milk in California: does BDE-209 transfer to breast milk? Environ Sci Technol 45:4579–4585.

Pérez-Maldonado, IN, Ramirez-Jimenez, M, Martinex-Arevalo LP, Lopez-Guzman, OD, Athanasiadou, M, Bergman, A, Yarto-Ramirex, M, Gavilan-Garcia A, Yanez, L, Diaz-Barriga, F. 2009. Exposure assessment of polybrominated diphenyl ethers (PBDEs) in Mexican children. Chemosphere 75:1215-1220.

Rawn, D. et al. 2011. Unpublished data. Canadian Health Measures Survey. Health Canada.

Rice DC, Reeve EA, Herlihy A, Zoeller RT, Thompson WD, Markowski VP. 2007. Developmental delays and locomotor activity in the C57BL6/J mouse following neonatal exposure to the fully-brominated PBDE, decabromodiphenyl ether. Neurotoxicol Teratol 29:511–520 [cited in US EPA, 2008].

Rice DC, Thompson WD, Reeve EA, Onos KD, Assadollahzahed M, Markowski VP. 2009. Behavioral changes in aging but not young mice after neonatal exposure to the polybrominated flame retardant decaBDE. Environ Health Perspect 117:1903–1911.

Roosens L, Abdallah MA-E, Harrad S, Neels H, Covaci A. 2009. Factors influencing concentrations of polybrominated diphenyl ethers (PBDEs) in students from Antwerp, Belgium. Environ Sci Technol 43:3535–3541.

Sandholm A, Emanuelsson B-M, Klasson-Wehler E. 2003. Bioavailability and half-life of decabromodiphenyl ether (BDE-209) in rat. Xenobiotica 33(11):1149–1158.

Schecter A, Päpke O, Joseph JE, Tung KC. 2005. Polybrominated diphenyl ethers (PBDEs) in U.S. computers and domestic carpet vacuuming: possible sources of human exposure. J Toxicol Environ Health A 68:501–513.

Schecter A, Päpke O, Harris TR, Tung KC, Musumba A, Olson J, Birnbaum L. 2006a. Polybrominated diphenyl ether (PBDE) levels in an expanded market basket survey of U.S. food and estimated PBDE dietary intake by age and sex. Environ Health Perspect 114:1515–1520.

Schecter A, Päpke O, Harris TR, Tung KC. 2006b. Partitioning of polybrominated diphenyl ether (PBDE) congeners in human blood and milk. Toxicol Environ Chem 88:319–324.

Schecter A, Colacino JA, Shah N, Päpke O, Opel M, Patel K, Birnbaum LS. 2010. Indoor and outdoor air PBDE levels in a southwestern US city. Toxicol Environ Chem 92:1053–1063.

Seyer A, Riu A, Debrauwer L, Bourgès-Abella N, Brunelle A, Laprévote O, Zalko D. 2010. Time-of-flight secondary ion mass spectrometry imaging demonstrates the specific localization of deca-bromo-diphenyl-ether residues in the ovaries and adrenal glands of exposed rats. J Am Soc Mass Spectrom 21:1836–1845.

Shanmuganathan D, Megharaj M, Chen Z, Naidu R. 2011. Polybrominated diphenyl ethers (PBDEs) in marine foodstuffs in Australia: residue levels and contamination status of PBDEs. Mar Pollut Bull 63:154–159.

She J, Holden A, Sharp M, Tanner M, Williams-Derry C, Hooper K. 2007. Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in breast milk from the Pacific Northwest. Chemosphere 67(9):S307–S317.

Shibutani M, Fujimoto H, Woo GH, Inoue K, Takahashi M, Nishikawa A. 2011. Reply to comment on “Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation.” Reprod Toxicol 32(3):375–378.

Shoeib M, Harner T, Ikonomou M, Kannan K. 2004. Indoor and outdoor air concentrations and phase partitioning of perfluoroalkyl sulfonamides and polybrominated diphenyl ethers. Environ Sci Technol 38:1313–1320.

Siddique S, Xian Q, Abdelouahab N, Takser L, Phillips SP, Feng Y-L, Wang B, Zhu J. 2012. Levels of dechlorane plus and polybrominated diphenylethers in human milk in two Canadian cities. Environment International 39:50-55.

Sjodin A, Wong L-Y, Jones RS, Park A, Zhang Y, Hodge C, DiPietro E, McClure C, Turner W, Needham LL, Patterson DG Jr. 2008. Serum concentrations of polybrominated diphenyl ethers (PBDEs) and polybrominated biphenyl (PBB) in the United States population: 2003–2004. Environ Sci Technol 42:1377–1384.

Stapleton HM, Dodder NG. 2008. Photodegradation of decabromodiphenyl ether in house dust by natural sunlight. Environ Toxicol Chem 27:306–312.

Strandberg B, Dodder NG, Basu I, Hites RA. 2001. Concentrations and spatial variations of polybrominated diphenyl ethers and other organohalogen compounds in Great Lakes air. Environ Sci Technol 35:1078–1083.

Su Y, Hung H, Brice KA, Su K, Alexandrou N, Blanchard P, Chan E, Sverko E, Fellin P. 2009. Air concentrations of polybrominated diphenyl ethers (PBDEs) in 2002–2004 at a rural site in the Great Lakes. Atmos Environ 43:6230–6237.

Takigami H, Suzuki G, Hirai Y, Sakai S. 2008. Transfer of brominated flame retardants from components into dust inside television cabinets. Chemosphere 73:161–169.

Takigami H, Suzuki G, Hirai Y, Sakai S. 2009. Brominated flame retardants and other polyhalogenated compounds in indoor air and dust from two houses in Japan. Chemosphere 76:270–277.

TERA [Toxicology Excellence for Risk Assessment]. 2011. Report of the ITER Review Meeting on Literature Risk Values for Decabromodiphenyl Ether, TCDD, and Acrylamide: February 15-16, 2011. ITER Review Organized by Toxicology Excellence for Risk Assessment.

Ter Schure AFH, Larsson P, Agrell C, Boon JP. 2004. Atmospheric transport of polybrominated diphenyl ethers and polychlorinated biphenyls to the Baltic Sea. Environ Sci Technol 38:1282–1287.

Teshima R, Nakamura R, Nakamura R, Hachisuka A, Sawada J-I, Shibutani M. 2008. Effects of exposure to decabromodiphenyl ether on the development of the immune system in rats. J Health Sci 54:382–389.

Thomsen C, Stigum H, Froshaug M, Broadwell SL, Becher G, Eggesbo M. 2010. Determinants of brominated flame retardants in breast milk from a large scale Norwegian study. Environ Int 36:68–74.

Toms L-ML, Bartkow ME, Symons R, Paepke O, Mueller JF. 2009. Assessment of polybrominated diphenyl ethers (PBDEs) in samples collected from indoor environments in south east Queensland, Australia. Chemosphere 76:173–178.

Tseng LH, Lee CW, Pan MH, Tsai SS, Li MH, Chen JR, Lay JJ, Hsu PC. 2006. Postnatal exposure of the male mouse to 2,2',3,3',4,4',5,5',6,6'-decabrominated diphenyl ether: decreased epididymal sperm functions without alterations in DNA content and histology in testis. Toxicology 224:33–43 [cited in US EPA 2008].

Tseng LH, Li MH, Tsai SS, Lee CW, Pan MH, Yao WJ, Hsu PC. 2008. Developmental exposure to decabromodiphenyl ether (PBDE 209): effects on thyroid hormone and hepatic enzyme activity in male mouse offspring. Chemosphere 70:640–647.

Tseng LH, Hsu PC, Lee CW, Tsai SS, Pan MH, Li MH. 2011. Developmental exposure to decabrominated diphenyl ether (BDE-209): effects on sperm oxidative stress and chromatin DNA damage in mouse offspring. Environ Toxicol. 13(4) [Epub ahead of print].

Ucar Y, Traag W, Immerzeel J, Kraats C, van der Lee M, Hoogenboom R, van der Weg G, Cakirogullari GC, Oymael B, Kilic D. 2011. Levels of PCDD/Fs, PCBs and PBDEs in butter from Turkey and estimated dietary intake from dairy products. Food Addit Contam B 4:141–151.

Uemura H, Arisawa K, Hiyoshi M, Dakesh*ta S, Kitayama A, Takami H, Sawachika F, Yamaguchi M, Sasai S. 2010. Congener-specific body burden levels and possible determinants of polybrominated diphenyl ethers in the general Japanese population. Chemosphere 79:706–712.

[US EPA] US Environmental Protection Agency. 1997. Chapter 14. In: Exposure factors handbook (1997 final report), vol. 2. Washington (DC): US EPA. Report No.: EPA/600/002F a–c. [cited 2009 Aug].

[US EPA] US Environmental Protection Agency. 2007. Toxicological review for polybrominated diphenyl ethers (PBDEs) human health assessment. Final report. External peer review. February 2007. Washington (DC): US EPA, Office of Research and Development, Integrated Risk Information System (IRIS) Program.

[US EPA] US Environmental Protection Agency. 2008. Toxicological review of decabromodiphenyl ether (BDE-209) (CAS No. 1163-19-5) in support of summary information on the Integrated Risk Information System (IRIS). Washington (DC): US EPA.

[US EPA] US Environmental Protection Agency. 2010. An exposure assessment of polybrominated diphenyl ethers (PBDE) (final). Washington (DC): US EPA. Report No.: EPA/600/R-08/086F.

Van der Ven LTM, van de Kuil T, Leonards PEG, Slob W, Cantón RF, Germer S, Visser TJ, Litens S, Håkansson H, Schrenk D, van den Berg M, Piersma AH, Vos JG, Opperhuizen A. 2008a. A 28-day oral dose toxicity study in Wistar rats enhanced to detect endocrine effects of decabromodiphenyl ether (decaBDE). Toxicol Lett 179:6–14.

Van der Ven LTM, Slob W, Piersma AH, Leonards PEG, Hamers T, Sandholm. 2008b. Reply to Letter to the Editor: More on the toxicity of decabromodiphenyl ether – Response to Hardy et al. (2008). Toxicol Lett 182: 130-132.

Van Leeuwen SPJ, de Boer J. 2008. Brominated flame retardants in fish and shellfish--levels and contribution of fish consumption to dietary exposure of Dutch citizens to HBCD. Mol Nutr Food Res 52:194–203.

Venier M, Hites RA. 2008. Flame retardants in the atmosphere near the Great Lakes. Environ Sci Technol 42:4745–4751.

Viberg H. 2002. Personal communication. Comments regarding abstract from the 2nd International Workshop on Brominated Flame Retardants 2001 [Viberg et al. 2001b] to A. Lam, Existing Substances Division, Health Canada, Ottawa, dated November 29, 2002 [cited in Health Canada 2006].

Viberg H. 2009. Neonatal ontogeny and neurotoxic effect of decabrominated diphenyl ether (PBDE 209) on levels of synaptophysin and tau. Int. J. Devl. Neuroscience 27: 423–429.

Viberg H, Fredriksson A, Jakobsson E, Ohrn U, Eriksson P. 2001a. Brominated flame-retardant: uptake, retention and developmental neurotoxic effects of decabromo-diphenyl ether (PBDE209) in the neonatal mouse. Toxicologist 61:1034 [abstract] [cited in Health Canada 2006].

Viberg H, Fredriksson A, Jakobsson E, Orn U, Eriksson P. 2001b. Brominated flame retardants: uptake, retention and developmental neurotoxic effects of decabromodiphenyl ether (PBDE209) in the neonatal mouse. In: Abstracts of the 2nd International Workshop on Brominated Flame Retardants, May 14–16, Stockholm, Sweden. Stockholm (SE): AB Firmatryck [abstract] [cited in Health Canada 2006].

Viberg H, Fredriksson A, Jakobsson E, Orn U, Eriksson P. 2003. Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicol Sci 76:112–120 [cited in Health Canada 2006].

Viberg H, Fredriksson A, Eriksson P. 2007. Changes in spontaneous behavior and altered response to nicotine in the adult rat, after neonatal exposure to the brominated flame retardant, decabrominated diphenyl ether (PBDE 209). Neurotoxicology 28:136–142 [cited in US EPA 2008].

Viberg H, Mundy W, Eriksson P. 2008. Neonatal exposure to decabrominated diphenyl ether (PBDE 209) results in changes in BDNF, CaMKII and GAP-43, biochemical substrates of neuronal survival, growth, and synaptogenesis. Neurotoxicology 29:152–159.

Vizcaino E, Grimalt JO, Lopez-Espinosa M-J, Llop S, Rebagliato M, Ballester F. 2011. Polybromodiphenyl ethers in mothers and their newborns from a non-occupationally exposed population (Valencia, Spain). Environ Int 37:152–157.

Vorkamp K, Thomsen M, Frederiksen M, Pederson M, Knudsen LE. 2011. Polybrominated diphenyl ethers (PBDEs) in the indoor environment and associations with prenatal exposure. Environ Int 37:1–10.

Wang F, Wang J, Dai J, Hu G, Wang J, Luo X, Mai B. 2010. Comparative tissue distribution, biotransformation and associated biological effects by decabromodiphenyl ethane and decabrominated diphenyl ether in male rats after a 90-day oral exposure study. Environ Sci Technol 44:5655–5660.

Wang F, Wang J, Wang J, Mai B, Dai J. 2011. Response to comment on “Comparative tissue distribution, biotransformation and associated biological effects by decabromodiphenyl ethane and decabrominated diphenyl ether in male rats after a 90-day oral exposure study.” Environ Sci Technol 45(11):5062–5063.

Wang J, Kliks MM, Jun S, Li QX. 2010. Residues of polybrominated diphenyl ethers in honeys from different geographic regions. J Agric Food Chem 58:3495–3501.

Watanabe W, Tomomi S, Sawamura R, Hino A, Kurokawa M. 2008. Effects of decabrominated diphenyl ether (DBDE) on developmental immunotoxicity in offspring mice. Environ Toxicol Pharmacol 26:315–319

Watanabe W, Tomomi S, Sawamura R, Hino A, Konno K, Kurokawa M. 2010. Functional disorder of primary immunity responding to respiratory syncytial virus infection in offspring mice exposed to a flame retardant, decabrominated diphenyl ether, perinatally. J Med Virol 82:1075–1082.

Webster G et al. 2011. Unpublished data. Chemicals, Health and Pregnancy Study. University of British Columbia.

Wilford BH, Harner T, Zhu J, Shoeib M, Jones KC. 2004. Passive sampling survey of polybrominated diphenyl ether flame retardants in indoor and outdoor air in Ottawa, Canada: implications for sources and exposure. Environ Sci Technol 38:5312–5318.

Wilford BH, Shoeib M, Harner T, Zhu J, Jones KC. 2005. Polybrominated diphenyl ethers in indoor dust in Ottawa, Canada: implications for sources and exposure. Environ Sci Technol 39:7027–7035.

Williams AL, DeSesso JM. 2010. The potential of selected brominated flame retardants to affect neurological development. J Toxicol Environ Health B 13:411–448.

Wu K, Xu X, Liu J, Guo Y, Li Y, Huo X. 2010. Polybrominated diphenyl ethers in umbilical cord blood and relevant factors in neonates from Guiyu, China. Environ Sci Technol 44:813–819.

Wu N, Herrmann T, Paepke O, Tickner J, Hale R, Harvey E, La Guardia M, McClean MD, Webster TF. 2007. Human exposure to PBDEs: associations of PBDE body burdens with food consumption and house dust concentrations. Environ Sci Technol 41:1584–1589.

Wu Y, Yu YH, Chen DJ, Jiang HP. 2008. Effect of maternal BDE-209 exposure on the learning and memory ability of offspring rats and the dose–effect relation. J South Med Univ [Nan Fang Yi Ke Da Xue Xue Bao] 28:976–978 [in Chinese with English abstract.

Xing T, Chen L, Tao Y, Wang M, Chen J, Ruan DY. 2009. Effects of decabrominated diphenyl ether (PBDE 209) exposure at different developmental periods of synaptic plasticity in the dentate gyrus of adult rats in vivo. Toxicol Sci. 110: 401–410.

Zhang W, Cai Y, Sheng G, Chen D, Fu J. 2011. Tissue distribution of decabrominated diphenyl ether (BDE-209) and its metabolites in sucking rat pups after prenatal and/or postnatal exposure. Toxicology 283:49–54.

Zhang Z, Wang X, Zou L, Ding S, Zhai J. 2010. Oxidative stress of decabromodiphenylether in mice brain tissue. Chin J Ind Hyg Occup Dis 28(1–2):900–903.

Zhou J, Yu Y, Chen D, Zhong Y. 2010. Effects of maternal oral feeding of decabromodiphenyl ether (PBDE 209) on the humoral immunity of offspring rats. J Trop Med (Guangzhou) 10(3):276–279.

Zhu LY, Ma B, Hites RA. 2009. Brominated flame retardants in serum from the general population in northern China. Environ Sci Technol 43:6963–6968.