Complex mixture modeling organophosphate pesticides.
NIOSH 2006 Jan; :1-22
This project used a quantitative experimental and modeling approach to evaluate the potential impact that pesticide mixture exposures might have on agricultural workers, who are routinely exposed to insecticides. Pesticide interactions can share a common theme in which dosimeter and biological responses .are altered when mixtures modify absorption rates, extent of metabolism, tissue distribution, clearance or pharmacological action. Organophosphorus insecticides are of particular concern since they are widely utilized, are neurotoxic, and a number of biomonitoring studies have documented both occupational and non-occupational exposures in adults and children to multiple pesticides. The current risk assessment paradigm focuses on individual chemicals; however, exposure is primarily to mixtures where there is limited understanding of the health effects. Occupationally exposed agricultural workers, handle concentrated pesticide formulations and therefore have higher exposures. Exposure to chemical mixtures can involve complex "chemical soups" which are poorly characterized in terms of components, concentrations, exposure duration and routes, and the overall toxicological effect of the mixture is most likely unknown. These uncertainties in terms of exposure, dose and biological response create difficulty in determining realistic risk from occupational exposure to mixtures. The overall approach was to develop an experimental/modeling strategy to understand the impact of complex chemical mixtures on the toxicological response of organophosphorus pesticides. The approach focused on understanding both the pharmacokinetic (absorption, distribution, metabolism and excretion) and pharmacodynamic (cholinesterase inhibition) responses associated with individual and binary mixtures of organophosphorus insecticides. The project strategy integrated the development of physiologically based pharmacokinetic and pharmacodynamic models with the acquisition of focused in vitro and in vivo experimental data for model development and validation. The strength of this approach is that it can be used to identify the most critical factors (i.e. exposure timing, routes of exposure, lack of protective equipment) that contribute to occupational exposure to insecticides, and allow researchers and regulators to assess internal dose and biological response with greater confidence. This project resulted in the development, validation and application of computational models assessing dosimeter and biological response for individual and binary mixtures of insecticides in animal models and humans. This experimentation/modeling strategy can now be expanded to assess the impact of lifestyle choices and in particular the impact of co-exposures to routinely consumed pharmacologically active agents (ex. pharmaceuticals, alcohol and nicotine) that have the demonstrated potential to likewise modify metabolism and biological response to insecticides. Since a comprehensive toxicological evaluation of chemical mixtures is not feasible, it is reasonable to develop strategies that can be applied to classes of chemical agents that have similar metabolic and mode of action profiles. In this regard, the Environmental Protection Agency (EPA) has developed a framework for conducting cumulative risk assessments for organophosphorus and other pesticides that have a common mode of toxicological action. They have indicated that physiologically based pharmacokinetic modeling approaches represent the future direction for conducting cumulative dose-response risk assessments. In this regard, the EP A has identified the organophosphorus insecticide models that have been developed as part of this project as representing key initial components in this process.
Models; Phosphates; Pesticides; Insecticides; Exposure-levels; Metabolic-rate; In-vitro-studies; Dosimetry; Pesticides-and-agricultural-chemicals; In-vivo-studies; Agricultural-workers; Agricultural-chemicals; Farmers; Risk-analysis; Organo-phosphorus-compounds; Organo-phosphorus-pesticides
Charles Timchalk, Battelle Memorial Institute, Center for Biological Monitoring and Modeling, 902 Battelle Blvd., PO Box 999, Richland, W A 99352
Final Grant Report
Research Tools and Approaches: Exposure Assessment Methods
National Institute for Occupational Safety and Health
Battelle Memorial Institute, Richland, Washington