Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

• Published in: Toxicology and applied pharmacology 2011-12, Vol.257 (3), p.365-376
• Main Authors: Crowell, Susan Ritger, Amin, Shantu G., Anderson, Kim A., Krishnegowda, Gowdahalli, Sharma, Arun K., Soelberg, Jolen J., Williams, David E., Corley, Richard A.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Administration, Oral; Algorithms; Animals; Benzo(a)pyrene - administration & dosage; Benzo(a)pyrene - chemistry; Benzo(a)pyrene - pharmacokinetics; Benzo[a]pyrene; Benzopyrenes - administration & dosage; Benzopyrenes - chemistry; Benzopyrenes - pharmacokinetics; Biological and medical sciences; BIOLOGICAL PATHWAYS; BLOOD; BLOOD FLOW; Carcinogenesis, carcinogens and anticarcinogens; CARCINOGENS; Chemical agents; CHRYSENE; COMBUSTION; Dibenzo[def,p]chrysene; Environmental Pollutants - administration & dosage; Environmental Pollutants - chemistry; Environmental Pollutants - pharmacokinetics; Female; GLYCOLS; Injections, Intravenous; LIVER; LUNGS; Medical sciences; METABOLISM; METABOLITES; Mice; Models, Biological; NAPHTHALENE; PBPK modeling; PERFUSED TISSUES; POLYCYCLIC AROMATIC HYDROCARBONS; PUBLIC HEALTH; PYRENE; Rats; Rats, Sprague-Dawley; RODENTS; SIMULATION; Tissue Distribution; Toxicology; Tumors
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2011.09.020

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. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. ► We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). ► B[a]P model accurately predicts data from multiple sources over a wide dose range. ► DBC model was based on the B[a]P model as less chemical specific data is available. ► DBC model accurately predicted preliminary pharmacokinetic data. ► DBC model underscored data gaps on metabolism, binding and pharmacokinetics.