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Abstract
We evaluated the available pharmacokinetic data and human and animal toxicity data for 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) (CASRN 1163-19-5) with the objective of deriving a reference dose (RfD) based on the best available science. The available studies for deriving an RfD were first screened using the Klimisch criteria and further evaluated using the United States Environmental Protection Agency’s general assessment factors for data quality and relevance (i.e., soundness, applicability and utility, clarity and completeness, uncertainty and variability, and evaluation and review). The chronic 2-year dietary feeding study conducted by the United States National Toxicology Program (Citation, Technical Report Series No. 309) was selected for RfD derivation. Hepatocellular degeneration in male rats was chosen as the critical endpoint in the development of an RfD. For dose-response characterization, we applied benchmark-dose modeling to animal data and determined a point of departure (the 95% lower confidence limit for a 10% increase in hepatocellular degeneration) of 419 mg/kg-day for oral exposures. Based on the similar pharmacokinetic characteristics of BDE-209 across species, this value was converted to a human equivalence dose of 113 mg/kg-day by applying a dosimetric adjustment factor based on body weight scaling to the ¾ power. An oral RfD of 4 mg/kg-day was calculated by using a composite uncertainty factor of 30, which consisted of 10 for intraspecies uncertainty, 3 for interspecies uncertainty (i.e., 3 for toxicodynamics × 1 for toxicokinetics), and 1 for deficiencies with the database. We consider the RfD to be adequately protective of sensitive subpopulations, including women, their fetuses, children, and people with hepatocellular diseases.
Declaration of interest: MLH and TS are employed by Albemarle Corporation, a global specialty chemical manufacturer whose product line includes brominated flame retardants. MB has received honoraria from Albemarle Corporation for work in the past. No form of remuneration was provided for his work herein. The views and opinions expressed in this article are those of the authors and not necessarily those of Albemarle Corporation or the Institute of Public Health and Environmental Protection.
Notes
1For the purposes of this article, we refer to 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether as BDE-209 with an appropriate descriptor. For example, for the commercial product, we call this “commercial BDE-209.” Sometimes, for stylist reasons, decaBDE is used.
2One of the papers referenced by Mörck et al. (2003), Klasson Wehler et al. (1996), supports this. In that study, 2,2′,4,5,5′-pentachlorobiphenyl was said to be eliminated in the feces mainly as metabolites, “…a large proportion of which were covalently bound to macromolecules and lipids.” Sandholm et al. (2003) hint at this at p. 1155 when saying that the phenolic metabolites “…could be reversible binding to the thyroxine hormone transporting protein transthyretin.”
3The fraction absorbed after oral dosing was calculated by dividing the AUCoral by the AUCIV.
4Naval Medical Research Institute.
5Additions and Corrections, Environ Sci Technol 41:4486.
6These BCFs were derived by the method described by Huwe and Smith (2007) and their corrected data in , Additions and Corrections, Environ Sci Technol 41:4486. A BCF was not calculated for BDE-201, which was not detected in the test article.
7Cf. Supplementary Table 3 of Van der Ven et al. (2008). Epididymis weights (units not listed in publication) were reported as follows: control “0” = 1.21 ± 0.16; control “00” = 1.07 ± 0.11; high dose group = 1.04 ± 0.06. for seminal vesicle weights, the following values were reported: control “0” = 0.93 ± 0.28; control “00” = 1.14 ± 0.63; high dose group = 1.22 ± 0.26.
8Cf. Supplementary Table 8 reports the following for sum apolar retinoids (mg/g) in female rats: control “0” = 0.87 ± 0.11; control “00” = 1.06 ± 0.10; and high dose group = 0.99 ± 0.07. For sum apolar retinoids (mg), the following values are reported for female rats: control “0” = 7.1 ± 0.6; control “00” = 9.5 ± 1.5; and high dose group = 8.0 ± 0.9.
9Congener mixture identical with FR-300-BA.
10Median lethal concentration.
11Median lethal dose.
12This study was compliant with the US EPA guideline No. 870.3700 (EPA, 1998a), and the Organization for Economic Co-operation and Development (OECD) guideline study No. 414 (OECD, 2001).
13This study was conducted in accordance with the US EPA’s Good Laboratory Practice Standards (EPA, 1989), and OECD Principles on Good Laboratory Practice (OECD, 1998).
14We confirmed with the authors that they did not cull the litters and did not keep track of the number of pups/litter/group lost due to infanticide or the number of litters/group lost due to abandonment. The authors also confirmed that after weaning, pups were selected randomly from commingled litters, such that the authors did not know which pups came from which litters within a group (Banasik et al., 2009).
15Note: A similar request was submitted to the US EPA for data on Viberg et al. (2008), since a US EPA scientist was second author on the paper. The Agency responded as follows: “[n]either EPA nor [the second author] has ever possessed, had a copy, or had control over any raw data responsive to your request” (FOIA, 2008).
16BMD associated with a 10% response adjusted for background.
17BMD lower confidence limit 10%.
18Body weight.
19In a later publication, Huwe et al. (2008) concluded that reductive debromination of BDE-209 “…appears to be a minor mechanism in rats…,” but did not provide a numerical value. These authors also noted that using a mixture of PBDEs “…makes it impossible to determine whether debromination of any individual congeners has occurred.”
20Lower limit on effective dose10: the 95% lower confidence limit of the dose of a chemical needed to produce an adverse effect in 10% of those exposed to the chemical, relative to control.
21Animals in all groups that died prior to the occurrence of the first hepatic neoplastic nodule in either treated group (week 87) were removed and not included in the analyses based on the assumption that these animals had insufficient opportunity to develop neoplastic nodules (NRC, 2000).