At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on toluene. The presentation was made by Sylvia Talmage of Oak Ridge National Laboratory. The subcommittee recommends a number of revisions. The subcommittee will review the revised AEGLs draft at its next meeting.

General Comments

The TSD appears too long. It should be condensed.

The consideration to use PBPK modeling is appropriate. After review by NAC, the NAS/COT Subcommittee on AEGLs will review this approach. Some specific points to the PBPK presentation are listed below under Specific Comments.

In a recent publication (Tanaka et al., 2003. J. Med. Sci. 49:129-39), 19 symptoms related to CNS and autonomic nervous system are reported to occur upon exposure to low (15.3-31.5 ppm) concentrations of toluene. It is recommended to evaluate whether these include some symptoms which may serve as starting points for AEGL derivation and to include this study in Section 2.2.1 (page 20, line 22).

It would be desirable and hopefully possible for the justifications of the AEGL values to be more explicit. Thus, on one hand, the use of 200 ppm for AEGL-1 (page 82, line 12) appears too conservative. This exposure level is a threshold for altered performance of an extended series of certain complex psychophysiological tests by humans. If the AEGL-1 values are to be based on CNS depression, the 15-min 300 ppm NOAEL of Baelum et al. (1990) could be used in conjunction with PBPK modeling to extrapolate the shorter and longer exposure periods. Once a decision is reached about factoring exercise into derivation of AEGLs, this can also be accommodated by PBPK modeling.

On the other hand, an intraspecies uncertainty factor (UF) of 1 was used to derive AEGL-1, yet insufficient scientific support appears to be provided to justify a reduction of the standard UF of 10 to 1 (as if there were zero intraspecies uncertainty left).

The text says that the “preponderance of data as a weight of the evidence consideration indicates that an 8-hr exposure to 200 ppm would be without adverse effects for the general population” (page 7, lines 33-34). The discussion in the text (page 81, Section 5.3 Derivation of AEGL-1) is even more vague.

The study used as the basis for deriving the AEGL-2 values is weak and not supported well by the studies cited in the text. The primary study is by Gamberale and Hultengren (1972), where people were exposed to 700 ppm toluene for 20 min. It says that at this level, “only a very subtle effect on the CNS was observed during this short exposure” (page 83, lines 5-6). Given the numerous studies on toluene, it is surprising that this is the best study that could be found to derive AEGL-2.

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