Physiologically Based Pharmacokinetic Modeling for Chlorinated Paraffins in Rats and Humans: Importance of Biliary Excretion

摘要

Chlorinated paraffins (CPs) are chemicals with high production volumes that can accumulate at high levels in general populations. The pharmacokinetics of CPs as pollutants is unknown, and there is no evidence that the medium chain chlorinated paraffins (MCCPs) and long chain chlorinated paraffins (LCCPs) are safe replacements for short chain chlorinated paraffins (SCCPs). In this study, SCCPs, MCCPs, and LCCPs were first in vivo and in vitro exposed to rat and liver microsomes, respectively. Toxicokinetics of these compounds were assessed and used to establish the corresponding physiologically based pharmacokinetic (PBPK) models in rats. More than 90% of ingested CPs were deposited in the liver and fat, and the compounds were extremely resistant to metabolism and mostly eliminated via biliary excretion. Then, humans' external and internal exposures to CPs were investigated for one year in Shenzhen, South China. The results were used to calibrate the key parameters for the establishment of a PBPK model in humans. In the PBPK models of rats and humans, the rate of biliary excretion had the greatest influence on the accumulated levels and half-lives of CPs. The body half-lives of human were estimated to be 5.1, 1.2, and 0.6 years for SCCPs, MCCPs, and LCCPs, respectively, suggesting the high accumulation of SCCPs in humans compared to other CPs.