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ToxSci Advance Access published online on November 17, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfi039
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received August 17, 2004
Accepted November 8, 2004

Biotransformation and Toxicokinetics

On the Importance of Exposure Variability to the Doses of Volatile Organic Compounds

S. M. Rappaport 1*, L. L. Kupper 2, and Y. S. Lin 1

1 Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7431
2 Department of Biostatistics, School of Public Health, University of North Carolina, Chapel Hill, NC 27599-7431

* To whom correspondence should be addressed.
S. M. Rappaport, E-mail: smr{at}unc.edu


  Abstract

The connection between occupational exposure to volatile organic compounds (VOCs) and the resulting internal doses is complicated by variability in air levels from day to day and by nonlinear kinetics of metabolism. We investigated long-term liver doses of VOCs and their metabolites using a physiologically based toxicokinetic model, to which 10,000 random 8-h exposures were inputted. Three carcinogenic VOCs were studied, i.e., benzene, perchloroethylene, and acrylonitrile; these compounds are all bioactivated in the liver and represent a wide range of an important toxicokinetic parameter (Vmax/QL·KM). For each VOC, simulations were performed using mean air concentrations (µX) between 0.0003 and 1 mg/l (which covers both linear and saturated metabolism) and using coefficients of variation of exposure (CVX) between 0.23 and 2.18 (which includes most occupational settings). Two long-term measures of internal dose were examined, i.e., the area under the liver concentration-time curve (AUCL) and the area under the metabolic rate-time curve (AURC). Interestingly, both AUCL and AURC were linear functions of cumulative exposure (CE, mg·h/l air) even when metabolism was saturated and CVX was large. Yet, at a given CE, both AUCL and AURC were affected by CVX, with the magnitude of the effect increasing with Vmax/QL·KM (i.e., perchloroethylene < benzene < acrylonitrile). Nonetheless, the effects of CVX were typically only a few percent and should be of little consequence unless a VOC has large values of Vmax/QL·KM, µX, and CVX. We conclude that CE should be a sufficient predictor of the dose of either the parent chemical (VOC) or its metabolite in the liver, even when metabolism is nonlinear. We also observed that AUCL and AURC were sensitive to changes in values of model parameters in the high-variability scenarios, suggesting that (when CVX is large) the population variability of AUCL and AURC can be quite large at a fixed CE.


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