Exposure estimation using repeated blood concentration measurements

Abstract

Physiologically based toxicokinetic (PBTK) modeling has been well established to study the distributions of chemicals in target tissues. In addition, the hierarchical Bayesian statistical approach using Markov Chain Monte Carlo (MCMC) simulations has been applied successfully for parameter estimation. The aim was to estimate the constant inhalation exposure concentration (assumed) using a PBTK model based on repeated measurements in venous blood, so that exposures could be estimated. By treating the constant exterior exposure as an unknown parameter of a four-compartment PBTK model, we applied MCMC simulations to estimate the exposure based on a hierarchical Bayesian approach. The dataset on 16 volunteers exposed to 100 ppm (%0.538 mg/L) trichloroethylene vapors for 4 h was reanalyzed as an illustration. Cases of time-dependent exposures with a constant mean were also studied via 100 simulated datasets. The posterior geometric mean of 0.571, with narrow 95% posterior confidence interval (CI) (0.506, 0.645), estimated the true trichloroethylene inhalation concentration (0.538 mg/L) with very high precision. Also, the proposed method estimated the overall constant mean of the simulated time-dependent exposure scenarios well with slightly wider 95% CIs. The proposed method justifies the accuracy of exposure estimation from biomonitoring data using PBTK model and MCMC simulations from a real dataset and simulation studies numerically, which provides a starting point for future applications in occupational exposure assessment.

Exposure reconstruction using a physiologically based toxicokinetic model with cumulative amount of metabolite in urine: a case study of trichloroethylene inhalation

“…The PBTK model parameter estimates were also obtained with small GSDs. When compared with the results using repeated blood concentrations of TCE (Chen et al 2010), the posterior GSDs were slightly higher than expected, which might have resulted from the simplified metabolic pathway and additional variations in the metabolite measurements. However, the advantage of avoiding repeated invasive blood sampling far surpassed the slight loss in precision.…”

“…The simulated C inh estimated the true inhalation concentration of 0.538 mg/l very well, with a geometric mean (GM) of 0.532 (median 0.532) mg/l and a 95% CI (0.441-0.645), in contrast with the GM of 0.571 mg/l and 95% CI (0.506-0.645) found when using repeated venous blood concentrations (Chen et al 2010). Because many more uncertainties are involved with using the metabolite TCOG in urine, the slightly wider 95% CI than that found by using the parent chemical TCE in blood is still satisfactory.…”

“…By using a series of mass-balance differential equations to describe the processes of absorption, distribution, metabolism, and elimination after chemical exposure at certain concentrations, a physiologically based toxicokinetic (PBTK) model can be applied to relate exposure to the target tissue dose through biomarker concentrations. Therefore, using reverse dosimetry, a PBTK model can be applied to reconstruct exposure using biomarker measurements, a method proven successful in other case studies (Allen et al 2007;Chen et al 2010;Georgopoulos et al 2009;Lyons et al 2008;Tan et al 2007). …”

“…Assessing environmental exposures to pollutants over time is of great importance to environmental epidemiology studies and health risk assessments (Chen et al 2004(Chen et al , 2010Maxwell and Kastenberg 1999;Mutshinda et al 2008), helping to protect the public and safeguard occupational health. However, detailed exposure information is seldom available and is often confounded by interindividual and spatiotemporal variations.…”

“…To reconstruct exposure using a PBTK model, a large number of model parameters need to be fitted, which may be reliably estimated using repeated blood measurements with Markov chain Monte Carlo (MCMC) simulations (Bernillon and Bois 2000;Bois et al 1996;Bois 2000;Chen et al 2010;Gelman et al 1996). However, due to the invasive nature of the procedure, it is not feasible to collect a representative sample of repeated blood measurements from the study population within a period as short as 24 h. On the other hand, using a single blood sample to retrospectively estimate population exposure (Allen et al 2007;Lyons et al 2008) may be inappropriate if the half-life of the exposure chemical is on the order of hours, such as the case for benzene or trichloroethylene (TCE).…”