Use of Physiologically Based Pharmacokinetic Models to Establish Biological Exposure Indexes

Abstract

This paper presents a simulation modeling approach to establish biological exposure indexes (BEIs) from ambient occupational exposure limits (OELs). A physiologically based pharmacokinetic (PB-PK) model was used to describe the disposition of volatile organic chemicals in the human. The model was used to simulate an exposure regimen similar to a typical work schedule. Exposure concentrations were set to equal the ambient OELs of the corresponding chemicals. Chemical concentrations in the expired air and blood and concentrations of metabolites in the urine were estimated with the PB-PK model for this exposure condition. Because the OELs establish the criteria for ambient exposure to chemicals, the concentrations of chemicals or their metabolites in biological media resulting from exposure to the OELs would likewise define acceptable exposure standards. On the basis of this rationale and method, BEIs were developed for 13 common industrial organic chemicals.

Exposure estimation using repeated blood concentration measurements

“…However, both trajectories had a mean blood concentration over time similar to that of scenario A. Therefore, it is expected that the proposed method regarding exterior exposure as an unknown constant holds Brown et al (1997) b The value of alveolar ventilation was set equal to that of the cardiac output because the subjects were at rest condition during the study (Leung 1992) under such circumstances. Table 2 summarizes the averaged outcomes based on the 100 simulated datasets under each of the exposure scenarios with mean inhalation concentrations 0.538 mg/L (100 ppm) and 0.269 mg/L (50 ppm), respectively.…”

“…Because the subjects of the TCE inhalation experiment were at rest, their cardiac output rates Q cc were assumed to be equal to alveolar ventilation rates Q alv (Leung 1992), and the flow rates to each compartment were determined as follows:…”

Biological monitoring of controlled toluene exposure

“…They found that from <10% to >95% of workers were expected to be protected from overexposure to six solvents using current BEI values. Leung [45] used a PBK model to predict 13 toxicant concentrations in breath, blood, and urine, given occupational exposure at current limits. In the current study we used the observed distributions of six anthropometric parameters and a PBK model to determine pre-and postexposure toluene breath levels that would protect 97.5% of workers from exposure at levels exceeding 50 ppm.…”

A statistical assessment on the stochastic relationship between biomarker concentrations and environmental exposures

“…A common method to achieve this is by combining PBPK models with statistical simulation techniques to simulate realistic groups of workers in variable industrial environments with parameters following various statistical distributions. The variability thus observed in the biological indicators is then described for uncertainties in predicting the biomarkers a s well as estimate of r 2 b (Droz et al, 1989;Leung et al, 1992;Perbellini et al, 1990;Thomas et al 1996). Although empirically plausible, major difficulties in unknown metabolic and kinetic rates limit its validity in prediction.…”

“…In addition, the true relationship may be masked by inter-individual differences (Thomas et al 1996). As an alternative, dynamic internal concentrations may be calculated and simulated by a PBPK model, in which the body is subdivided into anatomical compartments representing individual organs or tissue groups (Leung and Paustenbach 1988;Leung 1992;Perbellini et al 1990; Thomas et al 1996). The transfer of chemicals between these compartments is then described using mass balance differential equations that incorporate the blood flows, partition coefficients, and tissue volumes distributions (Thomas et al 1996).…”