Population physiologically based pharmacokinetic modeling for the human lactational transfer of PCB-153 with consideration of worldwide human biomonitoring results

Abstract

Background: One of the most serious human health concerns related to environmental contamination with polychlorinated biphenyls (PCBs) is the presence of these chemicals in breast milk.

Objectives: We developed a physiologically based pharmacokinetic model of PCB-153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB-153. Data in the literature provided estimates for model development and for performance assessment.

Methods: We used physiologic parameters from a cohort in Taiwan and reference values given in the literature to estimate partition coefficients based on chemical structure and the lipid content in various body tissues. Using exposure data from Japan, we predicted acquired body burden of PCB-153 at an average childbearing age of 25 years and compared predictions to measurements from studies in multiple countries. We attempted one example of reverse dosimetry modeling using our PBPK model for possible exposure scenarios in Canadian Inuits, the population with the highest breast milk PCB-153 level in the world.

Results: Forward-model predictions agree well with human biomonitoring measurements, as represented by summary statistics and uncertainty estimates.

Conclusion: The model successfully describes the range of possible PCB-153 dispositions in maternal milk, suggesting a promising option for back-estimating doses for various populations.

Keywords: PCB-153; body burden; exposure reconstruction; human milk biomonitoring; lactational transfer; physiologically based pharmacokinetic modeling; polychlorinated biphenyls; reverse dosimetry.

Figure 1

Five-compartment model of PCB-153 transfer during lactation.

Figure 2

Derivation of input exposure dose for PBPK modeling of loading body burden of PCB-153 in a 25-year-old woman. BW, body weight.

Figure 3

PCB-153 body-burden predictions for 1 of the 1,000 model simulations. In this model, we assumed that mammary tissue develops at 13 years of age and that lactation begins at age 25.

Figure 4

Mean and range of concentrations of PCB-153 in plasma (^a), serum (^b), and whole blood (^c) of populations from worldwide geographic locations. Data from Covaci et al. (2002) for Belgium and Rusiecki et al. (2005) for India; all other data from Minh et al. (2006).

Figure 5

Histogram of model simulations (right) compared with global measurements of PCB-153 in breast milk (left). The uncertainty in the model predictions results from uncertainty in the daily PCB-153 intake and in milk lactation rate. The blue circle in the model simulation bar chart indicates the mean prediction. Data from Abraham et al. (1998), Germany; Angulo et al. (1999), Spain; Dewailly et al. (1994), Canadian Inuits; Glynn et al. (2001), Norway; Greizerstein et al. (1999), Canada A and B, Mohawk, Quebec, New York A and B, Netherlands A and B, Lithuania, France, Norway B, Germany A and B; Inoue et al. (2006), Japan; Jaraczewska et al. (2006), Poland; Patterson et al. (1994), Sweden; Polder et al. (2003), Russia; Vartiainen et al. (1997), Finland; and Wittsiepe et al. (2007), Germany C.

Figure 6

Breast milk PCB-153 concentrations from Canadian Inuit populations compared with the simulated PCB-153 milk concentration generated using the median oral intake dose of 0.0068 μg/kg/hr from Akutsu et al. (2005) and the simulated estimated Inuit dose of 0.294 μg/kg/hr.

Figure 7

Time courses of PCB-153 concentrations in milk from lactating mothers from various countries. New York State data are from Schecter et al. (1998); each number 1 indicates the milk concentration value and time of sampling for six lactating women. Data for Germany are from Abraham et al. (1998), and the numbers 2, 3, and 4 represent time course data from three lactating women. Data for Spain are from Ramos et al. (1997), and numbers 5 and 6 indicate time course data for two lactating women. Xs represent single data points for 20 lactating women in Taizhong hospital in Taiwan.