全氟碳化合物在大鼠和人類依生理依據之藥物動力學模型研究

Abstract

Perflourinated compounds (PFCs), a group of perflourinated straight or branched carbon-chain organic fatty acids, are of great interest in health concern due to their abundance in the environment and biota all over the world and their potential toxic effects in humans and animals. Humans are exposed to PFCs from various media, including water consumption, particularly, residents living near to contaminated areas. In this work, human health risks derived from the exposure to PFCs through water consumption were assessed for different age groups of general population in Taiwan using probabilistic approach. Based on available data on concentrations of PFCs in river water, exposure to PFOS, PFOA and PFDA via water consumption for different age groups were estimated using deterministic and probabilistic risk assessment methods. The oral non-cancer risks from PFOS, PFOA and their combination, expressed as a Hazard Index (HI), was determined by comparing oral exposure dose (through water intake) with the oral Reference Dose (RfD). The average exposure to PFOS PFOA and PFDA via water consumption for adults ranged from 0.16 to 220.15, 0.43 to 12.5 and 0.43 to 2.36 ng kg-bw-1 day-1 and for children 0.13 to 354.3, 0.35 to 20.17 and 0.35 to 3.79 ng kg-bw-1 day-1, respectively. Probabilistic values of total HIs for all age groups reside near to Keya River exceed the RfD 2.4 to 4.8 times, corresponding mainly to PFOS with a percentage of 97%. In summary, children aged 1 to 3 years old and the residents reside near to Keya River are at the highest risk of exposure to PFCs via water consumption. In this assessment, considering that HI was calculated for only PFOS and PFOA due to the limited available recommended RfD of PFCs, we might underestimate risk for PFCs, but those residents could be at greater risk due to exposure to total PFCs due to water consumption. Although, PFOA and PFOS were most widely studied and a PBPK model have been constructed for them previously, this work developed the model for longer-carbon chain PFAAs, which were less studied, but, of growing great concern in risk assessment of exposure, due to their increasing environmental emissions and bioaccumulation in wildlife. To help risk assessment of PFCs in reducing this uncertainty and broadening the scope for other PFCs, I aimed to develop a physiologically based pharmacokinetic model (PBPK) for long carbon-chain PFAAs, including PFUnDA and PFDoDA, in rats and extrapolated to humans. My previous experience in developing a PBPK model for aristolochic acids (AA-I and II) and their active metabolites, aristolactams (AL-I and II) in rats used for parameter estimation, e.g. calculating tissue:blood partition coefficients using the unified algorithm and the modeling for PFAAs. A structure of a PBPK model for PFAAs, constructed on the bases of the experience in modeling for AAs, was time-dependent and flow-limited and consists of five essential compartments: liver as a target organ for liver recirculation and protein binding of PFAAs, richly perfused tissues, poorly perfused tissues, adipose, and kidney as a specific tissue for the excretion. Model development and simulation were performed by using software packages of MATLAB and Simulink graphical user interface (GUI). Tissue:blood partition coefficients were estimated based on the method of unified algorithm developed by Peyret et al. 2010. Michaelis-Menten kinetic parameters were used to describe the binding to liver protein and renal excretion and reabsorption, and the corresponding parameters were estimated by fitting the model. The developed models were validated by comparing the model predictions with the measured blood concentration time-course data for corresponding chemicals at the different dose levels. A PBPK model for PFUnDA and PFDoDA in rats have been developed for the first time and validated. This new rat PBPK model is able to be used in the assessment of risk associated with human exposure predicting the internal dose of PFUnDA and PFDoDA at the target organs of human body and toxicokinetic behavior of the chemicals through interspecies extrapolation. The interspecies extrapolation of rat PBPK model was successfully done for both PFUnDA and PFDoDA using the interspecies allometric scaling in the physiological parameters of the human body and some adjustments in the chemical-specific biochemical parameters.