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. We 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 during our initial funding cycle. 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. We included studies with the prototypic PAH commonly encountered in Superfund sites, benzo[a]pyrene (BaP), because of similar modes of action that will allow us to compare potencies based upon internal doses in target tissues. In this renewal, we will extend our 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 for extrapolating the risk of carcinogenesis to relevant human exposures.
Four specific aims are proposed to achieve this goal: (1) determine 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;(2) conduct focused in vivo pharmacokinetic studies with BaP, DBC and metabolites and impact of mixtures in rats and mice;(3) determine the functional activity of enzymes important to PAH metabolism as a function of species, tissue and life stage;and (4) continue 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.
The proposed research addresses 2 of the 4 mandated SRP research areas involving the development of advanced techniques for the detection, assessment, and evaluation of health effects and methods to assess the risks to human health. By completing these Aims, we will provide stakeholders with state-of-the-art quantitative and integrative tools that reduce the uncertainties associated with extrapolating from animal models, across dose, life stage, and route of exposure, to relevant human exposures.
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|Truong, Lisa; Bugel, Sean M; Chlebowski, Anna et al. (2016) Optimizing multi-dimensional high throughput screening using zebrafish. Reprod Toxicol 65:139-147|
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