Toxicological Sciences 2007 98(2):607-609; doi:10.1093/toxsci/kfm163
Brain Uptake, Pharmacokinetics, and Tissue Distribution in the Rat of Neurotoxic N-Butylbenzenesulfonamide
doi:10.1093/toxsci/kfm057
Toxicological Sciences 97, 253–264, 2007
The following corrections were requested because some symbols were not reproduced correctly. The corrections do not affect the analysis or interpretation of the data as originally published.
Legend to Figure 2 (on page 254)
The published text was missing superscripts and subscripts and should read as follows:
EI mass spectra of native NBBS (top; y-axis = relative abundance) and [2H9]NBBS (bottom; y-axis = relative abundance). The molecular ion of native NBBS corresponds to m/z 213 and the molecular ion of [2H9]NBBS corresponds to m/z 222. The ions used for quantitative analysis are m/z 170 (corresponding to NBBS), m/z 172 (corresponding to [2H9]NBBS), and m/z 176 (corresponding to [13C6]NBBS). The fragmentation of [13C6]NBBS is identical to that of NBBS and produces ions six mass units higher than the native compound.
Sentence under the heading 'Pharmacokinetics and distribution of NBBS in peripheral tissues (protocol 3)' (line 203 on page 255)
The text should read as follows:
At various times up to 24 hours, blood (400 µL) was collected (into microcentrifuge tubes containing heparin) for assay and the animals were then sacrificed with an iv dose of sodium pentobarbitone (200 mg/kg).
Formula under the paragraph headed ‘Octanol-water partition analysis and equilibrium dialysis (protocol 4).’ (on page 255)
The published formula has subscripts ‘NBSS’. These should be ‘NBBS’ (as follows):
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The second formula under the paragraph headed ‘Cerebrovascular permeability analysis.’ (on page 256)
The published formula begins with ‘PA’. This should be ‘PS’ (as follows):
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The formula under the paragraph headed ‘Pharmacokinetic analysis.’ (on page 256)
The published formula is incorrect (everything has been subscripted). It should read as follows:
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The sentence immediately after the formula above (line 295 on page 256)
The text should read as follows:
Minim (version 3.0.1 for Macintosh computers) was used for curve fitting and the function was fit to the data using unweighted logarithmic least-squares (Gauss-Newton-Marquardt method).
A sentence in the last paragraph under the heading 'Pharmacokinetic analysis.' (line 316 on page 256)
The text should read as follows:
The values used for residual plasma volumes were obtained from Altman and Dittmer (1971): 92 µL/g (for kidney); 99 µL/g (for liver) and 4 µL/g (for muscle and fat).
Subscript symbols in Table 6 (on page 259)
The symbols in the first three lines underneath 'Pharmacokinetic parameters' (column 1 of the table) should read as follows:
t1/2 
1 (min)
t1/2 2 (min)
t1/2 3 (min)
Text of the first paragraph immediately underneath the heading 'Discussion' (lines 507–515 on pages 260–261)
The text should read as follows:
Prior to the commencement of these studies, key aspects of the pharmacology of NBBS - the cerebrovascular permeability, brain distribution and pharmacokinetics of the sulfonamide plasticiser - had not been characterised. The toxicity of NBBS was, however, well established: (i) rabbits injected intracisternally with doses higher than 10 µg (per animal) developed a progressive spastic myelopathy, and (ii) oral exposure to water containing NBBS (at a level of 83 µg/mL) was sufficient to elicit progressive neurotoxicity and death in rabbits (Strong et al., 1991).
The text underneath the heading ‘Are There Risks Associated with Human Exposure to NBBS?’ (on page 262–263)
The text should read as follows:
lines 703–715
Progressive spastic myelopathy in New Zealand White rabbits only occurs following doses of NBBS greater than 10 µg (ic; Strong et al., 1991). Within 2–3 weeks of the initial administration, hyperreflexia is observed; thereafter, symptoms of progressive neurodegeneration are observed. The neurological deficits apparent with monthly ic treatment of rabbits with doses of upto 100 µg of NBBS (ic) could not, however, be induced more rapidly by repeated ip injections at an increased dosage (200 mg/kg; Strong et al., 1991). In fact, comparable deficits were only induced with ip doses of 300 mg/kg or higher (three times weekly) in rabbits.
lines 730–775
The neurotoxicity of NBBS also appears to be route specific. Motor dysfunction was induced with NBBS in the rat only after repeated 6-hourly doses (300 mg/kg, ip), but even then, the effects were of short duration, and the animals appeared to recover when dosing ceased (Lee et al., 1995). With accurate pharmacokinetic data, an assessment can be made of whether an ip dose of 300 mg/kg administered three times per week results in identical or higher brain NBBS concentrations than that achieved by monthly ic doses of upto 100 µg.
The assessment rests on the following assumptions: (1) the volume of CSF is 14% of transcellular fluid (TF) volume; (2) TF volume is 2.5% of total body water (TBW); (3) rabbit TBW is 735 ml/kg (Altman and Dittmer, 1971), and (4) rabbit blood volume is 60 ml/kg (Altman and Dittmer, 1971). The rabbits used by Strong and et al. (1991) weighed 2 kg. Therefore, the values for TBW and blood volume of these rabbits would have been 1470 and 120 ml, respectively. CSF volume would have been 5 ml (1470 x 2.5% x 14%). The final doses in CSF used by Strong and colleagues would have ranged from (10 µg [ic] or 2 µg/ml to 100 µg [ic] or 20 µg/ml).
Our results indicate that following a 1-mg/kg (iv) dose in rats, the concentration of NBBS achieved in CSF, 1 min following administration, is 200 ng/ml (the lowest neurotoxic dose used by Strong and colleagues was 2000 ng/ml; CSF). Assuming that the pharmacokinetics of NBBS in the rabbit and rat are similar (i.e., only ca. 2% of the administered dose remains 1 min following administration), a dose of 300 mg/kg administered ip to 2-kg rabbits would have resulted in a blood concentration of 100 µg/ml (600 mg/120 ml x 2%). The concentration in CSF would have been 30 µg/ml (as the CSF:blood concentration ratio is 0.3). This is approximately the concentration attained by a direct ic injection of 100 µg of NBBS.
This calculation shows that, in absolute terms, more NBBS is required to induce symptoms of neurodegeneration by ip rather than by ic administration; in other words, the toxic potential of the plasticizer is actually reduced as a result of ip administration. This is a good indicator that NBBS may be subject to first-pass metabolism (ip dosing approximates oral dosing in that the liver is not bypassed). Incubation of rat, rabbit, and human liver S9 fractions (post-mitochondrial supernatant) containing NBBS did reveal the presence of a 
-1 alcohol (2-hydroxy-N-butylbenzenesulfonamide; unpublished observations); however, further studies of the bioavailability and biotransformation of the plasticizer are warranted.
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