| Title: | Comparison of in vivo derived and scaled in vitro metabolic rate constants for several volatile organic compounds (VOCs) |
| Author(s): | Kenyon EM; Eklund C; Pegram RA; Lipscomb JC; |
| Address: | "Center for Computational Toxicology and Exposure, U.S. EPA, Office of Research and Development, Research Triangle Park, NC, United States. Electronic address: kenyon.elaina@epa.gov. Center for Computational Toxicology and Exposure, U.S. EPA, Office of Research and Development, Research Triangle Park, NC, United States. U.S. EPA, United States" |
| DOI: | 10.1016/j.tiv.2020.105002 |
| ISSN/ISBN: | 1879-3177 (Electronic) 0887-2333 (Print) 0887-2333 (Linking) |
| Abstract: | "Metabolic rate parameters estimation using in vitro data is necessary due to numbers of chemicals for which data are needed, trend towards minimizing laboratory animal use, and limited opportunity to collect data in human subjects. We evaluated how well metabolic rate parameters derived from in vitro data predict overall in vivo metabolism for a set of environmental chemicals for which well validated and established methods exist. We compared values of VmaxC derived from in vivo vapor uptake studies with estimates of VmaxC scaled up from in vitro hepatic microsomal metabolism studies for VOCs for which data were available in male F344 rats. For 6 of 7 VOCs, differences between the in vivo and scaled up in vitro VmaxC estimates were less than 2.6-fold. For bromodichloromethane (BDCM), the in vivo derived VmaxC was approximately 4.4-fold higher than the in vitro derived and scaled up VmaxC. The more rapid rate of BDCM metabolism estimated based in vivo studies suggests other factors such as extrahepatic metabolism, binding or other non-specific losses making a significant contribution to overall clearance. Systematic and reliable utilization of scaled up in vitro biotransformation rate parameters in PBPK models will require development of methods to predict cases in which extrahepatic metabolism and binding as well as other factors are likely to be significant contributors" |
| Keywords: | "Allyl Compounds/*pharmacokinetics Animals Hydrocarbons, Chlorinated/*pharmacokinetics Male Metabolic Clearance Rate Models, Biological Propane/*analogs & derivatives/pharmacokinetics Rats, Inbred F344 Volatile Organic Compounds/*pharmacokinetics Biotransf;" |
| Notes: | "MedlineKenyon, Elaina M Eklund, Christopher Pegram, Rex A Lipscomb, John C eng EPA999999/ImEPA/Intramural EPA/ Comparative Study England 2020/09/19 Toxicol In Vitro. 2020 Dec; 69:105002. doi: 10.1016/j.tiv.2020.105002. Epub 2020 Sep 15" |
