Experimental Toxicology Division
Pharmacokinetics Branch Projects

The mission of the Pharmacokinetics Branch is to understand the pharmacokinetics of environmental chemicals in the context of their human exposures and their potential toxicological effects. This understanding is then used to develop models and methods to quantitatively describe the relationship between exposure, dose and response. The ultimate goal is to use these models and methods in human health risk assessments.

HBCD is a specific class of brominated flame retardants, added to a variety of products ranging from thermal insulation building materials, upholstery textiles, and electronics in an effort to reduce the likelihood of the product igniting as well as increasing flash-over time. Concern for the effects of HBCD has increased significantly in recent years as their presence has been detected in environmental samples and in human tissues at steadily increasing concentrations. In predicting human health risks posed by HBCD, it is therefore necessary to accurately predict systemic dosimetry or the fate of these chemicals. The research will focus on the pharmacokinetics in an animal model. These studies will provide data that can be used in a PBPK model. This will aid in determining pharmacokinetic parameters in other mammalian systems as well as contributing to assessing human health risk of these chemicals. This project also includes Linda Birnbaum, from the Immediate Office.

This is a cross-ORD project which evaluates the potential health effects of pyrethroid pesiticides and looks to see if a cumulative risk assessment is appropriate. Research in PKB focuses on the development of exposure-doseresponse-models as part of this assessment. This will be done by 1) developing exposure-dose-response models for individual and mixtures of pyrethroids in rodents; 2) scaling the models for human exposure; and 3) applying the human models to estimate cumulative risk to pyrethroids. This project is in collaboration with the National Exposure Research Laboratorv.

The population of older Americans is increasing due to the aging of the "Baby Boomers," as well as increased life spans. A number of physiological and biochemical changes occur during aging which could impact the relationship between exposure, dose, and response to environmental chemicals. These changes could result in altered sensitivity of the elderly to environmental contaminants. In order to evaluate whether the elderly are at altered risk to these chemicals requires studies that focus on basic principles of susceptibility, using prototype chemicals. Research in PKB focuses on the physiological and biochemical changes associated with aging that impact pharmacokinetics. These efforts will then allow for an initial understanding of the influence of pharmacokinetic differences between the elderly and other populations.

Activation of hepatic nuclear receptors results in the induction of xenobiotic metabolizing enzymes which are involved in the catabolism of thyroid hormones. In rats and mice, activation of these receptors results in hypothyroidism. This project focuses on the differences in thyroid catabolism of different species, using primary hepatocytes from rodents and humans. These efforts should aid in extrapolating dose response relationships for thyroid hormone disruptors from rodents to humans.

This project involves refinement and application of physiologically-based pharmacokinetic (PBPK) models for multiple species (mouse, rat, and human) to understand the relationship between measures of dose to target tissue and toxic response and the factors influencing it. This includes linkage to biologically-based dose response (BBDR) models and exposure models, as well as evaluation of the impact of known polymorphisms on-target tissue dosimetry and thus potential risk of arsenic-induced disease.