Institute for Risk Assessment Sciences, Toxicology Division, Utrecht University, P.O. Box 80176, NL-3508 TD Utrecht, The Netherlands
To the Editor:
Viberg et al. (2003b) report neurobehavioral effects of the flame retardant decabromodiphenyl ether (PBDE 209). The effects consist of changes in spontaneous behavior, which appear to become more intense for at least six months after a single oral dose of 20.1 mg/kg BW to neonatal mice on PND 3 (Viberg et al., 2003b
). PBDE 209 is reported to accumulate in brain during the first week after administration. Unfortunately, the exact concentration of PBDE 209 in the brain remains ambiguous, since there appears to be some inconsistency in the published figures or in the units of concentrations. In the text, the authors state that after dosing 20.1 mg/kg BW on PND 3, the amount of PBDE 209 in brain on PND 10 amounts to 388 pmol (p. 119; Viberg et al., 2003b
). However, Table 1 reports 42.8 nmol PBDE 209 equivalents in brain on PND 10 after dosing 1.5 MBq/kg BW of the radiolabeled [U-14C]PBDE 209, with a specific activity of 650 MBq/mmol. This seems impossible, since the total amount administered, which is calculated to be 13.8 nmol [U-14C]PBDE 209, is smaller than the amount reported to be present in the brain.
Even in the more favorable case, the amount of 388 pmol PBDE 209 in brain associated with the neurobehavioral effect appears to be rather high. Assuming that the mouse body weight is 6 g on PND 10 (Eriksson et al., 2002), brain volume is estimated to be 100 µl (Brown et al., 1997
) and the brain concentration of PBDE 209 is calculated to be 3.9 µM. Based on mouse brain lipid contents, i.e., 14% w/w or 14 mg (You and Dallas, 1998
), the amount of PBDE 209 in brain is equivalent to 26.6 µg/g lipid weight. This is three orders of magnitude higher than the highest levels of PBDEs found in human tissues (Sjödin et al., 2003
). From a study with the pentabrominated PBDE 99 (Eriksson et al., 2002
), it is calculated that the effective dose of 8 mg/kg BW leads to a similar high brain concentration of 4.3 µM PBDE 99. Behavioral effects of the hexabrominated PBDE 153 have been reported to occur at similar doses (9 mg/kg BW at PND 10; Viberg et al., 2003a
).
Two questions remaining are whether environmental exposure might possibly lead to similar high tissue concentrations and, if this would be the case, whether the PBDEs will induce specific neurotoxic effects. The answer to the first question largely depends on how much is actually present in and available for uptake from the environment. This is a critical issue for the risk assessment of widely used chemicals in general and for those chemicals used in our living environment, like the flame retardants, in particular. However, the actual levels in human tissues found thus far appear to be several orders of magnitude lower than the amounts in mouse brain associated with neurobehavioral effects. The answer to the second question will require more detailed studies of the neurotoxic potential of PBDEs and of their structure-activity relation. In this respect it is remarkable that the decabrominated congener PBDE 209 (Viberg et al., 2003b) causes similar neurobehavioral effects as the hexa- and pentabrominated congeners (Eriksson et al., 2002
; Viberg et al., 2003a
) at similar dose levels. With receptor-mediated effects, such as that via the Ah receptor, an increase in number of halogens is almost invariably associated with a reduction in biological or toxicological response often by several orders of magnitude (Van den Berg et al., 1998
). Thus it can be questioned whether the neurobehavioral changes are indeed caused by an effect on a receptor with specific affinity for halogenated compounds, such as the Ah receptor. Up to date, only fragmentary and apparently incoherent data are available, e.g., the acute inhibition of dopamine uptake in rat brain synaptic vesicles in vitro by micromolar concentrations of the penta-BDE mixture DE-71 (Mariussen and Fonnum, 2003
), the apparent inability of the DE-71 mixture to affect LTP in perinatally exposed rats (Gilbert and Crofton, 2002
), and the delayed reduction of the number of bungarotoxin-sensitive nicotinic receptors in adult hippocampus by PBDE 153 after neonatal exposure (Viberg et al., 2003a
). Further investigation of the relative potencies or structure-activity-relationship of the PBDEs with respect to basic processes possibly underlying neurodevelopmental changes is required to substantiate the causal relations between PBDE exposure and neurobehavioral effects. In the meanwhile, the reported neurobehavioral effects will be of limited relevance for risk assessment, if only because they will remain subject to scientific debate.
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