RECONSTRUCTING WEEK-LONG EXPOSURES TO VOLATILE ORGANIC-COMPOUNDS USING PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELS

Reconstruction of human exposure to toxic chemicals using physiologica lly based pharmacokinetic (PBPK) models and biomarkers is an attractiv e prospect, because biomarker measurements generally provide the most direct evidence of dose. Previously it has been shown that it is possi ble to reconstruct short-term (30 minute) exposure to chloroform, and that it is possible in some cases to resolve the total dose between tw o routes of uptake (Georgopoulos et al., 1994). In this paper it is sh own that it is mathematically feasible to reconstruct longer term expo sures to volatile organic compounds (VOCs), using benzene as a paradig m for other VOCs, and exhaled breath concentration as a biomarker of e xposure. First, it is shown that exhaled breath concentration is an ap propriate biomarker for long-term exposure to benzene, since benzene a ccumulates in fat and is eliminated in exhaled breath. Application of a benzene PBPK model (Travis et al., 1990) showed that benzene continu es to accumulate in the fat compartment for over 10 days, and conseque ntly fat acts as an integrator of dose during this period. Second, the benzene PBPK model is used to reconstruct exposure using the maximum likelihood approach. Since no data were available for long-term exposu res of this duration, ''data'' with a normally distributed random erro r and 30% coefficient of variation were generated by the PBPK model fo r a variety of daily exposures. It was shown that in most cases it is possible to estimate cumulative exposure within 40% of the actual valu es, even when the exposure concentration-time profile is unknown. The estimated exposure is found to always be an under-estimate of the true exposure when the exposure concentration is assumed to be constant.