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DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS
Citation:
Pastoor, T. AND H A. Barton. DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS. Presented at Society of Toxicology, Baltimore, MD, March 21-25, 2004.
Description:
DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS
Pastoor, Timothy1, Barton, Hugh2
1 Syngenta Crop Protection, Greensboro, NC, USA.
2 EPA, Office of Research and Development-NHEERL, RTP, NC, USA.
A multi-stakeholder series of discussions developed a set of general considerations, recommendations, and specific strategies to help guide generation of useful pharmacokinetic (PK) data in agricultural chemical testing. The value of this information is predicated on determining the relationship between the concentration of free compound in plasma and the biological/toxicological response. Careful, tier-wise collection of PK data would better define dose across route, frequency, and duration of exposure as well as across species and life stages. The recommendations include:
" Develop basic kinetic data early, before or in conjunction with initial toxicity testing.
" Generate more focused kinetic data based on results of endpoint-specific toxicity studies. Once toxicity data become available, then the kinetics data should be revisited to aid in interpretation and development of an understanding of mode of action (MOA) and dose-response relationships. More focused kinetic data will define a systemic dose (versus administered dose) and provide a logical means to establish route-specific reference doses.
" Collect appropriate kinetics data from repeated toxicity studies. The purpose of such studies is to clearly understand the disposition of a compound in the body, improve understanding of its disposition after multiple dosing and, ultimately, to be able to define systemic dose for a variety of dosing scenarios.
" Obtain human kinetics data to validate and compare with animal data. Kinetic studies, coupled with PK modeling, converts administered dose into an "internal" dose that can be compared from animals to humans. Integrate Dose and Response. Tying tissue dose metrics and mode of action (MOA) together has the potential to lead to more rational and accurate health risk assessments.