Mixture Modeling: Pesticide Drug Interactions

描述（由申请人提供）：本研究项目涉及开发一种实验和建模方法，以评估吸烟和饮酒对经常接触杀虫剂的农业工人的影响（即额外风险）。药物/化学品相互作用有一个共同的主题，即当化学混合物改变吸收速率、代谢、组织分布、清除率和药理作用时，药代动力学和药效学反应会发生改变。据推测，烟草制品的使用和酒精饮料的消费在潜在的活性剂量（与正常的使用模式）可以影响关键的代谢和动态过程，修改剂量测定和生物反应后，急性和重复接触杀虫剂。在农药中，像毒死蜱这样的有机磷杀虫剂特别令人关注，因为它们被广泛使用，具有神经毒性，一些研究记录了成人和儿童的职业和非职业接触。有机磷杀虫剂的作用方式涉及其抑制乙酰胆碱酯酶（AChE）活性的能力，导致乙酰胆碱在胆碱能突触内积累，从而产生广泛的神经毒性反应。以前，对该项目的研究导致了杀虫剂（毒死蜱和二嗪农）的基于生理学的药代动力学和药效学（PBPK/PD）模型的开发和验证。这些模型被证明可以准确地模拟大鼠和人类的剂量测定和胆碱酯酶抑制。该延续项目将侧重于扩展该研究，以评估先前暴露于烟草/尼古丁和乙醇的影响。该方法的基本原理是基于与常规使用烟草和乙醇相关的已知高暴露以及尼古丁和乙醇改变代谢的能力，可能影响杀虫剂剂量测定。此外，已知尼古丁和乙醇会影响胆碱能受体（烟碱和毒蕈碱）功能，这也是有机磷杀虫剂的关键药效学靶标。该项目将评估生物和代谢变化、目标组织剂量测定以及与烟草/尼古丁和乙醇共同接触后对这些农药的动态反应。研究结果将被纳入一个计算框架，以定量评估杀虫剂暴露对健康的影响。人类细胞体外实验数据的开发代表了一个重要的替代人类实验模型系统，其结果也将被整合到建模框架中，以帮助预测对人类健康的影响。完全可以预期，这种方法将有助于理解各种复杂的化学相互作用，因为它涉及到与杀虫剂一起工作的职业健康影响。

DESCRIPTION (provided by applicant): This research project involves the development of an experimental and modeling approach to evaluate the impact (i.e. additional risk) that smoking and alcohol consumption has on agricultural workers who are routinely exposed to insecticides. Drug/chemical interactions share a common theme in which pharmacokinetic and pharmacodynamic responses are altered when chemical mixtures modify absorption rates, metabolism, tissue distribution, clearance and pharmacological action. It is hypothesized that the use of tobacco products and the consumption of alcoholic beverages at pharmacologically active doses (associated with normal use patterns) can influence key metabolic and dynamic processes modifying dosimetry and biological response following both acute and repeat exposures to insecticides. Among pesticides, organophosphorus insecticides like chlorpyrifos have been of particular concern since they are widely utilized, are neurotoxic, and a number of studies have documented both occupational and non-occupational exposures in adults and children. The mode of action for organophosphorus insecticides involves their capacity to inhibit acetylcholinesterase (AChE) activity resulting in the accumulation of acetylcholine within the cholinergic synapse thereby producing a wide range of neurotoxic responses. Previously, research on this project resulted in the development and validation of physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for insecticides (chlorpyrifos and diazinon). These models were shown to accurately simulate dosimetry and ChE inhibition in both rats and humans. This continuation project will focus on extending that research to evaluate the impact of prior exposure to tobacco/nicotine and ethanol. The rationale for this approach is based on the known high exposures associated with routine use of tobacco and ethanol and the capability of nicotine and ethanol to modify metabolism potentially impacting insecticide dosimetry. Additionally, nicotine and ethanol are known to impact cholinergic receptor (nicotinic and muscarinic) function which is also a key pharmacodynamic target for organophosphorus insecticides. The project will assess biological and metabolic changes, target tissue dosimetry, and dynamic responses to these pesticides following co-exposures with tobacco/nicotine and ethanol. The results will be integrated into a computational framework to quantitatively assess the health implications from insecticide exposures. The development of experimental in vitro data in human cells represents an important surrogate human experimental model system and the results will likewise be integrated into the modeling framework to help predict health effects in humans. It is fully anticipated that this approach will facilitate the understanding of a variety of complex chemical interactions as it relates to the occupational health implications of working with insecticides.