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EVALUATION OF ALTERED SENSITIVITY OF OLDER ADULTS TO ENVIRONMENTAL AGENTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING
Citation:
DEVITO, M. J., M. V. EVANS, M. S. OKINO, B. R. SONAWANE, CHADWICK M. THOMPSON, L. S. BIRNBAUM, K. YOKLEY, C. CORTON, J. LEE, AND A. M. GELLER. EVALUATION OF ALTERED SENSITIVITY OF OLDER ADULTS TO ENVIRONMENTAL AGENTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING. Presented at U.S. EPA 2006 Science Forum, Washington, DC, May 16 - 18, 2006.
Description:
The population of older Americans is increasing due to the aging of the Baby Boomers as well as an increase in the average life span. A number of physiological and biochemical changes occur during aging that could influence the relationship between exposure, dose, and response to environmental chemicals. These changes could result in altered sensitivity of the elderly to environmental contaminants. Environmental contaminants encompass a broad spectrum of chemical structures and toxicities. To evaluate whether the elderly are at altered risk to these chemicals requires studies that focus on basic principles of susceptibility using prototype chemicals. Researchers at the National Health and Environmental Effects Research Laboratory (NHEERL), National Center for Environmental Assessment (NCEA), and National Exposure Research Laboratory (NERL) have developed a novel approach to address this issue for a series of prototype chemicals through use of physiologically based pharmacokinetic (PBPK) models. PBPK models quantify the relationship between exposure and target tissue dose using mathematical descriptions of the physiological and biochemical processes involved. Using PBPK models for prototype chemicals, the models can be parameterized to describe older adult men and women and the relationship between exposure, and target tissue dose can be evaluated and compared with younger adults and children. These efforts will then allow for an initial understanding of the influence of pharmacokinetic differences between the elderly and other populations. These studies will also provide the basis for prioritizing studies on potential pharmacodynamic susceptibility of the elderly.
This evaluation consists of several projects. The first collaborative project, which includes researchers from NCEA, NHEERL, and NERL, is the development of a database of the physiological changes that occur with age for use in PBPK models. The second project focuses on understanding which physiological and biochemical parameters are most important in a PBPK model for prototype environmental chemicals. This approach applies sensitivity analysis to the PBPK model to determine which parameters play critical roles in these models. Once the critical parameters are defined, parameter values from younger and older adults will be compared to predict whether older adults are likely to show altered sensitivity to these prototype chemicals. This second collaborative project is between researchers from the Environmental and Occupational Health Science Institute (EOSHI) at Rutgers University and researchers at NHEERL and NERL. A third project examines the biochemical and gene expression changes in liver and blood of older adults. The impact of these changes on the pharmacokinetics of environmental chemicals will be evaluated using the PBPK models.
The results of this program will aid in our understanding of the role of pharmacokinetics in the altered sensitivity of older adults. The use of prototype chemicals and PBPK models will provide insight into the biological basis of the altered sensitivity. By understanding the biological basis of the pharmacokinetic differences, we can better assess the potential for altered sensitivity in older adults to a broad range of environmental chemicals.