Translating dosimetry of Dibenzo[def,p]chrysene (DBC) and metabolites across dose and species using physiologically based pharmacokinetic (PBPK) modeling.

Autor: Pande P; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA., Madeen EP; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA., Williams DE; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA., Crowell SR; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA., Ognibene TJ; Lawrence Livermore National Laboratory, Livermore, CA 94550, USA., Turteltaub KW; Lawrence Livermore National Laboratory, Livermore, CA 94550, USA., Corley RA; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA., Smith JN; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA; Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA. Electronic address: jordan.smith@pnnl.gov.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2022 Mar 01; Vol. 438, pp. 115830. Date of Electronic Publication: 2021 Dec 18.
DOI: 10.1016/j.taap.2021.115830
Abstrakt: Dibenzo[def,p]chrysene (DBC) is an environmental polycyclic aromatic hydrocarbon (PAH) that causes tumors in mice and has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Animal toxicity studies often utilize higher doses than are found in relevant human exposures. Additionally, like many PAHs, DBC requires metabolic bioactivation to form the ultimate toxicant, and species differences in DBC and DBC metabolite metabolism have been observed. To understand the implications of dose and species differences, a physiologically based pharmacokinetic model (PBPK) for DBC and major metabolites was developed in mice and humans. Metabolism parameters used in the model were obtained from experimental in vitro metabolism assays using mice and human hepatic microsomes. PBPK model simulations were evaluated against mice dosed with 15 mg/kg DBC by oral gavage and human volunteers orally microdosed with 29 ng of DBC. DBC and its primary metabolite DBC-11,12-diol were measured in blood of mice and humans, while in urine, the majority of DBC metabolites were obeserved as conjugated DBC-11,12-diol, conjugated DBC tetrols, and unconjugated DBC tetrols. The PBPK model was able to predict the time course concentrations of DBC, DBC-11,12-diol, and other DBC metabolites in blood and urine of human volunteers and mice with reasonable accuracy. Agreement between model simulations and measured pharmacokinetic data in mice and human studies demonstrate the success and versatility of our model for interspecies extrapolation and applicability for different doses. Furthermore, our simulations show that internal dose metrics used for risk assessment do not necessarily scale allometrically, and that PBPK modeling provides a reliable approach to appropriately account for interspecies differences in metabolism and physiology.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: