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|Title||Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Crowell SRitger, Amin SG, Anderson KA, Krishnegowda G, Sharma AK, Soelberg JJ, Williams DE, Corley RA|
|Journal||Toxicol Appl Pharmacol|
|Administration, Oral, Algorithms, Animals, Benzo(a)pyrene, Benzopyrenes, Environmental Pollutants, Female, Injections, Intravenous, Mice, Models, Biological, Rats, Rats, Sprague-Dawley, Tissue Distribution|
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude.
|Alternate Journal||Toxicol. Appl. Pharmacol.|
|PubMed Central ID||PMC3226888|
|Grant List||P42 ES016465 / ES / NIEHS NIH HHS / United States |
P42 ES016465-01A1 / ES / NIEHS NIH HHS / United States