Variability in Biological Exposure Indices Using Physiologically Based Pharmacokinetic Modeling and Monte Carlo Simulation

Abstract

By using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation, the interindividual variability in the concentrations of chemicals in a worker's exhaled breath and urine were estimated and compared with existing biological exposure indices (BEIs). The PBPK model simulated an exposure regimen similar to a typical workday, while exposure concentrations were set to equal the ambient threshold limit values (TLVs) of six industrial solvents (benzene, chloroform, carbon tetrachloride, methylene chloride, methyl chloroform, and trichloroethylene). Based on model predictions incorporating interindividual variability, the percentage of population protected was derived using TLVs as the basis for worker protection. Results showed that current BEIs may not protect the majority or all of the workers in an occupational setting. For instance, current end-expired air indices for benzene and methyl chloroform protect 95% and less than 10% of the worker population, respectively. Urinary metabolite concentrations for benzene, methyl chloroform, and trichloroethylene were also estimated. The current BEI recommendation for phenol metabolite concentration at the end-of-shift sampling interval was estimated to protect 68% of the worker population, while trichloroacetic acid (TCAA) and trichloroethanol (TCOH) concentrations for methyl chloroform exposure were estimated to protect 54% and 97%, respectively. The recommended concentration of TCAA in urine as a determinant of trichloroethylene exposure protects an estimated 84% of the workers. Although many of the existing BEIs considered appear to protect a majority of the worker population, an inconsistent proportion of the population is protected. The information presented in this study may provide a new approach for administrative decisions establishing BEIs and allow uniform application of biological monitoring among different chemicals.