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ToxSci Advance Access originally published online on January 19, 2005
Toxicological Sciences 2005 85(1):460-467; doi:10.1093/toxsci/kfi091
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Toxicological Sciences vol. 85 no. 1 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Validation of Human Physiologically Based Pharmacokinetic Model for Vinyl Acetate Against Human Nasal Dosimetry Data

P. M. Hinderliter*,1, K. D. Thrall{dagger}, R. A. Corley{dagger}, L. J. Bloemen{ddagger} and M. S. Bogdanffy*

* Haskell Laboratory for Health and Environmental Sciences, E. I. du Pont de Nemours and Co., Newark, Delaware19714; {dagger} Battelle Pacific Northwest Laboratories, Biological Sciences Division, Richland, Washington 99352; {ddagger} Dow Benelux NV, Epidemiology, Health Services, Terneuzen, The Netherlands

Received October 13, 2004; accepted January 17, 2005

Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

Key Words: vinyl acetate; nasal dosimetry; PBPK modeling, human.


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