Development of physiologically based pharmacokinetic and pharmacodynamic models to determine dosimetry, dynamic response, and to assess risk following exposure to organophosphorous insecticides.
Timchalk C; Poet TS
Toxicologist 2005 Mar; 84(Suppl 1):273-274
There is an ongoing need to develop approaches for quantitatively assessing risk associated with exposures to a broad-range of organophosphorus insecticides and to determine the potential implications of these exposures to human health. These insecticides share common metabolic activation/detoxification pathways and a common mechanism of neurotoxicity associated with excessive cholinergic stimulation, due to the inhibition of acetylcholinesterase in nerve tissues. Efforts are underway to develop state-of-the-art physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling approaches to assess dosimetry and biological response following exposure to single organophosphorus insecticides or more complex mixtures. A PBPK/PD model has been developed for the organophosphorus insecticides chlorpyrifos and diazinon utilizing available data from rats and humans. These models have been extended to incorporate age- and polymorphism-dependent changes and have been successfully used to quantitatively determine the dose-dependent impact of insecticide exposure. Secondly, a binary PBPK/PD model has been developed to quantitatively assess dosimetry and response due to mixed exposures. This binary model facilitates understanding the mixture interactions and the potential for additivity, synergism or antagonism from multiple insecticide exposures. These results demonstrate that PBPK/PD modeling can be used to quantitatively assess exposure and biological response to classes of insecticides involving multiple routes of exposure (i.e. skin, ingestion, inhalation) that are routinely encountered in the environment. In summary, it is envisioned that once fully validated, these modeling approaches will be very useful for accessing exposure and health risk as a component of a broader biomonitoring or epidemiology assessment strategy for a wide range of potentially exposed individuals.
Pesticides; Pesticides-and-agricultural-chemicals; Pesticide-residues; Pest-control; Insecticides; Insecticide-poisoning; Metabolic-study; Metabolism; Metabolites; Agricultural-chemicals; Agricultural-industry; Agriculture; Pharmacodynamics; Laboratory-animals; Animals; Animal-studies; Organo-phosphorus-pesticides; Exposure-levels; Dosimetry; Blood-samples; Gas-chromatography; Models; Risk-analysis
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana
Battelle Memorial Institute, Richland, Washington