Impact/Purpose:

This research is aimed at characterizing intrahuman variability in susceptibility because of lifestage differences (e.g., very young, very old) in exposure or biological processes. It also addresses issues such as the long-term effects of developmental exposure to environmental agents through experimental animal research and prospective human data to understand the environmental contributions to human disease. This project focuses on the differential sensitivity of the elderly to environmental exposures. Its objectives are to determine the characteristics that define the aged as a susceptible subpopulation; determine pharmacokinetic (PK) and pharmacodynamic (PD) bases for differential responses of the elderly; and determine how susceptibility in the elderly varies across systems/tissues.

This research program seeks to examine whether there are special susceptibilities associated with the aged compared to the healthy young adult population. This research will generate data that will identify and prioritize those functions and mechanisms that most lead to exposure and age-related decline. By doing so, these studies will address the uncertainty of whether toxicity data collected in young adults provides a sufficient margin of safety to protect against effects that may result from toxic exposure to an aged individual. As such, it should move risk assessment toward more biologically-based decisions about uncertainty factors and help our understanding of how to appropriately incorporate the differential sensitivity of the aged into the current risk assessment framework of the US EPA.

Description:

SUMMARY: An important Agency mandate is to identify subpopulations particularly susceptible to adverse effects associated with exposure to environmental contaminants. For example, a critical public health question is the extent to which exposure to environmental contaminants contribute to the neurological impairments experienced by the aged. NTD’s successful experience in identifying and characterizing susceptibility of the fetus and child is now being focused on the this later life stage. This emerging area of research is being shaped substantially by the Division’s intention to integrate pharmacokinetic and pharmacodynamic characterization with the assessments of neurotoxic outcomes. This approach provides a sound foundation for incorporating characterization of susceptibility using contemporary genomics and proteomics. As an initial focus, this research is evaluating the hypothesis that alterations in neuronal excitability and cellular metabolism confer particular susceptibility to the aged from environmental contaminants and contributes to neurological impairments that are associated with later life stages. APPROACH: Older adults comprise a subpopulation that may have special susceptibilities to toxicant-induced dysfunction or degeneration due to the critical characteristics of their life-stage. The goal of this project is to understand whether responses to environmental insults differ in the aged compared to the young adult population. The candidate mechanisms driving age-related susceptibility that will be considered include: changes in pharmacokinetics, age-related alterations in cell signaling, deposition and accumulation of harmful metabolic by-products, natural decline in reserve capacity, cumulative gene replication error-induced alterations, changes in processes specific to the cell cycle, DNA repair, and cellular homeostasis, and response to oxidative stress. This project includes research in two of the major areas of concern to the aged population, cancer and degeneration in the nervous system. The project on carcinogenesis will bring to bear the many aspects of initiation, promotion, repair processes and homeostasis on the issue of the interaction between aging and toxicant-exposure leading to tumor production. The studies on neurodegeneration concentrate on age- and toxicant-induced changes in response and repair mechanisms in the central nervous system and in the visual system. Studies on response and repair mechanisms in the CNS will focus on differences in age- and toxicant-induced gene and protein expression in different brain regions to begin to understand the different processes that are associated with functional losses in these brain areas. The studies on ocular toxicity address the concern that pesticides may be an environmental risk factor, particularly to aging populations already susceptible to retinal degeneration. In addition, work on response and repair mechanisms in the CNS will be compared to similar work in other tissue systems in the cancer project to see if age-related changes in repair and homeostatic mechanisms are similar in these different tissue types. This will allow us to prioritize particular processes in particular systems.

Record Details: