Impact/Purpose:

This project focuses on how exposure, dose, and effect information can be incorporated into risk assessment methods to account for early life stages. It will identify approaches to address pharmacokinetic (PK) and pharmacodynamic (PD) issues related to extrapolation across windows of vulnerability in multiple species. This will provide options for risk assessment or for additional research to improve those risk assessments. This research will also define for developmental endpoints and chemical classes what risk assessment approaches are feasible for addressing windows of vulnerability and what additional work is required to reach a systematic set of guidelines for addressing these issues of interspecies extrapolation for exposure and dosimetry. Finally, the development of computer simulation models that can be parameterized for different species and developmental time periods will be useful for future development of guidelines dealing with PK and PD issues across different life stages.

The objectives of this project are to focus modeling and laboratory research around selected case studies including: volatile organics, organophophate pesticides, and conazoles; obtain physiological, biochemical, and anatomical parameters for rodents and humans for selected windows of vulnerability; quantify metabolism, and perhaps other pharmacokinetic (PK) processes such as absorption in humans and rodents for the selected windows of vulnerability with in vitro methods; develop physiologically based pharmacokinetic (PBPK) models and generate rodent PK data for the case study chemicals during the windows of vulnerability in rodents and humans; develop human exposure models during the windows of vulnerability to link to the PBPK models; and delineate the magnitude of age-related differences in sensitivity to pesticides and elucidate mechanisms (kinetic and/or dynamic) underlying this difference in sensitivity.

Description:

There are windows of vulnerability that exist during various life stages during which exposure to environmental chemicals may result in permanent damage to biological systems. These windows may exist at various stages of gestation, as well as postnatally, during infancy, childhood, or adolescence. One major source of uncertainty and potential source of error in the assessment of the health risk of children derives from developmental events occurring in different time periods for different species. This is particularly apparent for events that occur in the early postnatal (lactational) period for rodents and in utero for humans. Thus, lipophilic chemicals such as polychlorinated biphenyls (PCBs), which disrupt thyroid hormones, cause developmental hearing toxicity in rodents during the lactational period due to massive mobilization from the mother's fat reserves to her milk during lactation. This same effect would not likely occur following postnatal exposure in humans because hearing development occurs in utero. On the other hand, the situation would be reversed if a chemical were preferentially accumulated in the fetus. Clearly, extrapolations between animals and humans will be dependent upon the developmental processes at risk. Because animal toxicity data will continue to play an important role in the assessment of a chemical's potential to impact children's health, there is a need to develop a systematic approach to assess the relevance of animal toxicity data occurring during different developmental periods, both prenatal and postnatal, to humans and to extrapolate the response from animals to humans. This research will cover several activities, including: a review of the available literature, whose main objective is to develop a framework that includes exposure scenarios and PK processes associated with different windows of vulnerability to assess children's health risk from animal toxicity data; a determination of age-related PD changes, which will delineate the magnitude of age-related differences in sensitivity to pesticides and elucidate mechanisms (kinetic and/or dynamic) underlying this differential sensitivity; and an evaluation of developmental PK of a class of prototypic pesticides, specifically, conazoles.

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