Superfund Research Program
Cross-Species and Life Stage Comparisons of PAH Dosimetry
Project Leader: Jordan N. Smith (Pacific Northwest National Laboratory)
Grant Number: P42ES016465
Funding Period: 2009-2025
Project Summary (2013-2020)
Many polycyclic aromatic hydrocarbon (PAH) Superfund site contaminants are carcinogenic, some of which can cross the placenta to produce effects in offspring later in life. While metabolic activation to reactive intermediates is required for toxicity, little is known about the pharmacokinetics of PAHs and their metabolites in humans under real world exposure conditions. The research team therefore teamed with cancer biologists, chemists, and toxicologists in this SRP to develop the first physiologically based pharmacokinetic (PBPK) models for any high molecular weight carcinogenic PAHs capable of comparing species, tissue, and life stage differences in metabolic activation and detoxification processes in rats, mice, and humans.
This project initially focused upon the potent transplacental carcinogen, dibenzo[def,p]chrysene (DBC) which produces T-cell lymphomas, a common cancer for children and young adults, in the offspring of mice exposed to a single dose during pregnancy. The researchers included studies with the prototypic PAH commonly encountered in Superfund sites, benzo[a]pyrene (BaP), because of similar modes of action that will allow them to compare potencies based upon internal doses in target tissues. During this phase of the project, project researchers are extending their studies to evaluate the disposition of key metabolites at each stage of development, growth, and maturation and the impact of mixture exposures to improve the basis for extrapolating the risk of carcinogenesis to relevant human exposures.
To achieve this goal, the researchers are:
- Determining the comparative rates of in vitro metabolism of BaP, DBC and their major metabolites in rat, mouse and human tissues and the impact of mixture exposures
- Conducting focused in vivo pharmacokinetic studies with BaP, DBC and metabolites and impact of mixtures in rats and mice
- Determining the functional activity of enzymes important to PAH metabolism as a function of species, tissue and life stage
- Continuing to develop, evaluate and refine life stage-specific PBPK models for rats, mice and humans to provide stakeholders with quantitative tools for predicting risks to humans at relevant exposures.