Citation:

OKINO, M. S., M. V. EVANS, S. ISUKAPALLI, S. WANG, P. G. GEORGOPOULOS, M. KARSTADT, R. TORNERO-VELEZ, M. DEVITO, L. S. BIRNBAUM, J. N. BLANCATO, AND A. M. GELLER. EVALUATING RISK IN OLDER ADULTS USING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS. Presented at EPA Science Forum 2005, Washington, DC, May 16 - 18, 2005.

Impact/Purpose:

The overall goal of this work is to develop information to assess potential environmental health risks and susceptibility in the aging population. Initial work will be directed toward developing information that can be used to identify and characterize what is known about exposure, dose, and biological effects for key life stages in the aging population and to identify key data gaps to be addressed through further research. Work under this task may also incorporate or investigate elements of the cumulative exposure research plan for multiple stressors in potentially susceptible sub-populations and communities. Specific research objectives have been identified to address four discrete elements of the environmental paradigm for an aging population.

1) Identify key chemical and biological stressors in the aging population, compile extant information on exposures to these agents and the extent to which they may be different in aging and other populations, and identify key gaps in our knowledge of exposure to important stressors.

2) Identify the key life stages in the aging population with regard to exposures and susceptibilities to chemical and biological stressors. Compile activity pattern information for aging Americans in key life stages, including information on physical activity, time and location information, dietary intakes, and pharmaceutical use that may impact exposures and/or susceptibility. Identify key gaps in our knowledge of activities in subpopulations of the aging by life stages.

3) Identify important aging-related changes in pharmacokinetics and pharmacodynamics that may increase susceptibility to adverse effects from envrionmental stressors, develop pharmacokinetic models appropriate for susceptible subpopulations of the aging, and identify key gaps in knowledge of physiological processes in the aging.

4) Use the information developed for exposure, activity, and pharmacokinetics to extend existing source to dose models to aging populations and susceptible subpopulations at different life stages for use in risk assessment and identify key data gaps that must be filled to improve such models.

Description:

The rapid growth in the number of older Americans has many implications for public health, including the need to better understand the risks posed by environmental exposures to older adults. An important element for evaluating risk is the understanding of the doses of environmental toxicants that reach potential target organs and how long these toxicants dwell in the body. While some data exist on the responses of older adults to therapeutic medications, there are broad data gaps in our understanding of the determinants of dosimetry to toxicants in this subpopulation. Researchers in the ORD's National Health and Environmental Effects Research Laboratory (NHEERL) and NERL are collaborating with the EOHSI, a joint project of UMDNJ and the R.W. Johnson Medical School and Rutgers University, to produce physiologically based pharmacokinetic (PBPK) models that mathematically describe the physiology of older individuals in the context of chemical absorption, distribution, metabolism, and excretion (ADME). The ORD researchers have extensive experience in developing and applying PBPK models toward human health risk assessment; the EOHSI brings advanced computational methods required to determine which changes in model parameters most affect tissue dosimetry and toxicity for prototype toxicants. The representation of the physiological and biochemical pathways with these models allows for the evaluation of changes to the risk metrics as the effects of aging are implemented in the model. These effects may include decline in renal function, changes in tissue composition, and changes to metabolic enzymes due to age, health status, or medications. PBPK models will be developed for a diverse set of chemicals relevant to the diverse population of older adults. This research will identify characteristics that are associated with enhanced risk in older adults. These results will be used to predict who in the older adult subpopulation may be most susceptible and which toxicants present the greatest risks based on known changes in pharmacokinetics with age, disease, pharmaceutical use, and diet. This work will also help to identify areas on which future research should be focused to efficiently reduce uncertainties in risk assessment.

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