Description:

The overall objective of the proposed project is to develop and validate a systematic quantitative approach for reducing uncertainty in risk assessments of pesticide exposures of children. Vulnerability of infants and children may be the result of exposure during periods of: (a) sequenced biochemical and morphological events in growing tissues that alter pesticide pharmacodynamics; and (b) physiological and biochemical changes that affect the absorption and disposition of chemicals. The focus of the proposed project is on the latter category of events. Particular attention will be paid to maturation of: the GI mucosal barrier to absorption; the blood-brain barrier; plasma protein binding; tissue blood flows and volumes, including adipose tissue; and metabolism.

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(1) Use the results of pharmacokinetic experiments in adult rats with deltamethrin (DLM), a representative pyrethroid insecticide, and published physiological and biochemical parameter values to develop a physiologically-based pharmacokinetic (PBPK) model for DLM and its major metabolites in the mature animal. (2) Characterize maturational changes in major physiological and chemical-specific indices in developing rats. (3) Define the dose-dependent metabolism and kinetics of DLM in developing rats. Employ these data and the measured age-dependent physiological and biochemical indices to construct and validate a PBPK model appropriate for neonatal to sexually-mature animals. (4) Utilize the model to: (a) predict the internal dosimetry of DLM in developing animals; and (b) test hypotheses about the role of specific immaturities in altered target organ deposition (e.g., limited adipose tissue and metabolic capacity, coupled with increased oral absorption and blood-brain barrier penetration, result in greater deposition of DLM in the brain of neonates).

Cost :$749,991.00

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