Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling
- Resource Type
- Authors
- Harvey J. Clewell; Clive Meredith; Allison Franzen; Susan Crowell; Robinan Gentry; Jerry L. Campbell; Anne Loccisano; Cynthia Van Landingham; Michael Lumpkin
- Source
- Inhalation Toxicology
- Subject
- 0301 basic medicine
Physiologically based pharmacokinetic modelling
animal structures
Health, Toxicology and Mutagenesis
physiologically based pharmacokinetic model
Administration, Oral
010501 environmental sciences
Pharmacology
Toxicology
01 natural sciences
complex mixtures
Models, Biological
Article
03 medical and health sciences
chemistry.chemical_compound
Pharmacokinetics
Administration, Inhalation
medicine
polycyclic compounds
Benzo(a)pyrene
Dosimetry
Animals
Humans
Benzopyrenes
Lung
0105 earth and related environmental sciences
Inhalation Exposure
lung deposition
Inhalation
particle inhalation
organic chemicals
human dosimetry
Rats
Benzo[a]pyrene
030104 developmental biology
Renal Elimination
medicine.anatomical_structure
chemistry
embryonic structures
Carcinogens
Pyrene
Particulate Matter
Research Article
- Language
- English
- ISSN
- 1091-7691
0895-8378
Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities.