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TOLUENE EXPERIMENTAL EXPOSURES IN HUMANS: PHARMACOKINETICS AND BEHAVIOR
Citation:
Benignus, V A., P J. Bushnell, AND W K. Boyes. TOLUENE EXPERIMENTAL EXPOSURES IN HUMANS: PHARMACOKINETICS AND BEHAVIOR. Presented at Air Toxics Planning Meeting, Research Triangle Park, NC, June 11-12, 2002.
Description:
Toluene Experimental Exposures in Humans:
Pharmacokinetics and Behavioral Effects
(Ongoing Research)
Vernon A. Benignus1, Philip J. Bushnell2 and William K. Boyes2
Human subjects will be exposed to 250 and 500 ppm toluene for one hour in the Human Studies Division exposure chambers. The exposure levels have been selected to provide dose-effect curves for the acute effect of toluene on signal detection. During the exposure, blood toluene will gradually rise while the subject is performing the signal-detection task. Regression analysis will be used to fit logit models to the data which will contain observations from low doses to higher doses. Higher doses are required because (a) stable estimates are required for accurate curve estimation (b) lower-dose data are frequently marginally significant and a continuum of dose-related effects lend credibility to the findings (c) when combining doses of multiple solvent exposure, doses will be converted to potency-weighted toluene-equivalent sums which will require knowledge of higher toluene doses.
The first experiment will be to test and improve (if needed) a physiologically-based pharmacokinetic (PBPK) model for toluene in humans. This model will be used to (a) estimate internal doses during the signal-detection task performance and (b) for estimation of internal doses for environmental exposures. Internal dose cannot be measured in the signal detection experiment because blood drawing or breath sampling would interfere with task performance.
Subjects will perform the task during the PBPK experiment to obtain exploratory data and to make conditions for the dose estimates realistic. Symptoms will also be collected periodically to assure that subjects are being safely exposed.
The signal detection task will employ a task that was developed for rats and has been standardized for humans. Standardization data demonstrate that humans perform the task in the same way as rats. The task involves watching a signal light for small, short-duration increases in brightness. Such changes are reported upon request, by appropriate button presses. Subjects will perform the task intermittently for one hr during exposure and for one hr after exposure.
The status of this project is (a) signal-detection task development has been completed and results are being prepared for publication (b) all required human ethics protocols have been approved and (c) all exposure facility preparations have been made. Human exposures will begin as soon as blood analysis equipment is operational and human subjects can be recruited. This should be in late summer of 2002.
1US EPA, ORD, NHEERL, HSD
2US EPA, ORD, NHEERL, NTD