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Linking Exposure Science to Current and Future Pesticide Risk Assessment: From Biomonitoring to PBPK Modeling to High Throughput Screens
Citation:
MARTIN, S. A., T. J. SHAFER, M. DeVito, M. C. Fortin, B. Eskenazi, C. Lu, AND M. Bouchard. Linking Exposure Science to Current and Future Pesticide Risk Assessment: From Biomonitoring to PBPK Modeling to High Throughput Screens. Presented at Society of Toxicology Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
abstract for proposal for symposium, workshop sponsored by Society of Toxicology
Description:
Organophosphate (OP) and pyrethroid (PYR) pesticides are amongst the most widely used insecticides. While useful in their ability to control and remove insects from cattle, crops, and homes, they are inherently linked to varying degrees of toxicity as a result of their actions on cells, channels, and enzymes. OP and PYR are neurotoxic, acting primarily on acetylcholinesterase and voltage-gated sodium channels. For this reason, human exposure, especially the exposure of more susceptible subpopulations such as children and fetuses, is always a concern. Subtle alterations during these critical lifestages may lead to adverse health outcomes. Exposure science and toxicokinetic modeling enable quantification of the absorbed dose and determination ofthe target tissue dose, while research into toxicity pathways improves our understanding of the mechanisms by which these pesticides can alter development or function, and provides a rationale to engage the risk assessment process. By using analytical chemistry, the compounds of interest or their metabolites can be quantified in biological matrices or in the environment. These levels can in tum be fed into PBPK models that use life-stage and species specific physiological and biochemical descriptors to describe on a macro scale chemical transport and tissue disposition. This combination enables estimation of the target tissue doses that relate to nervous system associated pharmacodynamic endpoints. With knowledge of the dose-response and quantitative estimates of the dose, it is possible to develop informed risk assessments and to determine whether the current level of exposure within a surveyed population represents a risk. The integration of in vitro/in vivo data with pharmacokinetic and pharmacodynamic modeling provides a better understanding ofthe essential elements necessary for thorough human risk assessment and the adequate protection of the sensitive human populations. This session will culminate with two presentations that demonstrate this integration, through shared data between the speakers. One presentation will delve into novel high-throughput screening and prioritization methods that utilize in vitro animal and human cell lines to inform and guide future toxicity, biomonitoring, and modeling studies, while the second presentation will include PBPK model development and utilization of the data from high throughput methods. It is the integration of these scientific methods that are advancing our ability to facilitate and accommodate risk assessment needs. This is an abstract of a presentation and does not reflect EPA policy.