Goodman Julie E
Gradient Corporation, Health Sciences, Cambridge, MA 02138, USA.
Regul Toxicol Pharmacol. 2009 Jun;54(1):91-104. doi: 10.1016/j.yrtph.2009.02.006. Epub 2009 Feb 26.
On June 30, 2008, the US EPA's IRIS updated their toxicological review on the 2,2',4,4',5,5',6,6'-decabromodiphenyl ether congener and published a revised oral RfD of 0.007mg/kg day based on a NOAEL for neurobehavioral effects of 2.22mg/kg day, as reported by Viberg, H. et al., 2003b. Neurobehavioral derangements in adult mice receiving decabrominated diphenyl ether (PBDE 209) during a defined period of neonatal brain development. Toxicol. Sci. 76, 112-120 (Comment in: Toxicol. Sci. (2004) 2079, 2205-2206, author reply 2207-2208, Comment in: Toxicol. Sci. (2004) 2081, 2528-2529)], and a total uncertainty factor of 300. To evaluate IRIS' updated RfD, we conducted a weight-of-evidence analysis of developmental neurobehavioral effects. The evidence consists of four studies from two laboratories [Viberg et al., 2003b; Viberg, H. et al., 2007. Changes in spontaneous behaviour 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; Johansson, N. et al., 2008. Neonatal exposure to decabrominated diphenyl ether (PBDE 209) causes dose-response changes in spontaneous behaviour and cholinergic susceptibility in adult mice. Neurotoxicology; Rice, D.C. et al., 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]. The reported effects from these laboratories were in opposite directions - Rice et al. (2007) found mice treated with 20mg/kg day BDE-209 initially had higher activity and an increased habituation, while the Viberg group reported mice and rats treated with >or=20mg/kg BDE-209 (Viberg et al., 2003b, 2007) or mice treated with 2mg/kg BDE-209 (Johansson et al., 2008) had lower initial activity and decreased habituation (although inappropriate statistical methods may have affected results). There was also an overall lack of effects noted in the Functional Observational Battery conducted by Rice et al. (2007). Thus, the Viberg et al. (2003b) study, even in conjunction with other studies, is not suitable for establishing an RfD for BDE-209 or the commercial decabromodiphenyl ether product.
2008年6月30日，美国环境保护局综合风险信息系统（IRIS）更新了对2,2',4,4',5,5',6,6'-十溴二苯醚同系物的毒理学审查，并发布了修订后的经口参考剂量（RfD），即每日0.007毫克/千克，该数值基于Viberg等人于2003年发表的研究中所报告的2.22毫克/千克/日的神经行为效应无观察到有害作用水平（NOAEL）[Viberg, H.等人，2003b。新生小鼠脑发育特定时期接受十溴二苯醚（PBDE 209）后的神经行为紊乱。《毒理学科学》76, 112 - 120（评论见：《毒理学科学》(2004) 2079, 2205 - 2206，作者回复2207 - 2208，评论见：《毒理学科学》(2004) 2081, 2528 - 2529）]，以及总不确定系数300。为评估IRIS更新后的RfD，我们对发育神经行为效应进行了证据权重分析。证据包括来自两个实验室的四项研究[Viberg等人，2003b；Viberg, H.等人，2007。新生大鼠在新生期暴露于溴化阻燃剂十溴二苯醚（PBDE 209）后成年期自发行为的变化及对尼古丁反应的改变，《神经毒理学》28, 136 - 142；Johansson, N.等人，2008。新生期暴露于十溴二苯醚（PBDE 209）导致成年小鼠自发行为和胆碱能敏感性的剂量反应变化。《神经毒理学》；Rice, D.C.等人，2007。新生期暴露于全溴化PBDE十溴二苯醚后C57BL6/J小鼠的发育延迟和运动活动，《神经毒理学与致畸学》29, 511 - 520]。这些实验室报告的效应方向相反——Rice等人（2007）发现每日接受20毫克/千克BDE - 209处理的小鼠最初活动水平较高且习惯化增加，而Viberg团队报告每日接受≥20毫克/千克BDE - 209处理的小鼠和大鼠（Viberg等人，2003b，2007）或每日接受2毫克/千克BDE - 209处理的小鼠（Johansson等人，2008）最初活动水平较低且习惯化降低（尽管不恰当的统计方法可能影响了结果）。Rice等人（2007）进行的功能性观察组合测试中也未观察到总体效应。因此，即使结合其他研究，Viberg等人（2003b）的研究也不适合用于确定BDE - 209或商用十溴二苯醚产品的RfD。
