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

Journal Article · · Toxicology and Applied Pharmacology
 [1];  [2];  [2];  [1];  [3];  [3];  [1];  [4]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  2. Oregon State Univ., Corvallis, OR (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Oregon State Univ., Corvallis, OR (United States)
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We report that 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.

Research Organization:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS)
Grant/Contract Number:
AC52-07NA27344; P42 ES016465; R01 ES028600; 5R24GM137748; AC05-76RL01830
OSTI ID:
1860816
Report Number(s):
LLNL-JRNL-832577; 1050235
Journal Information:
Toxicology and Applied Pharmacology, Vol. 438, Issue N/A; ISSN 0041-008X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
polycyclic aromatic hydrocarbon (PAH)
dibenzo[def
p]chrysene (DBC)
physiologically based pharmacokinetic (PBPK) modeling
interspecies extrapolation
Internal dose-metrics