Non-Invasive Biological Monitoring of Pesticides

描述(由申请人提供)：在阐述21世纪毒性测试的愿景时，国家研究委员会(NRC)指出，暴露科学将发挥关键作用。在这种情况下，生物监测是将内部剂量与可测量的影响定量联系起来的关键组成部分。还有人提出，准确评估化学暴露以及生物影响的流行病学研究将具有最有意义的解释，从而产生最大的影响。在流行病学研究中进行生物监测的一个主要障碍是缺乏使用唾液等微创生物流体测量化学暴露的快速、现场可部署的定量技术。我们最近完成的研究导致了农药传感器平台的开发，一个用于快速表征唾液中农药摄取和清除的体内动物模型系统，以及一个基于唾液测量的预测全身剂量的剂量学模型。最近，通过测量农药制造厂工人唾液中的目标分析物，证实了该传感器的用途。该项目非常成功，可作为评估更广泛的重要化学品的框架。由于人类很少接触单一试剂，而是接触复杂的混合物，因此需要开发能够测量多个分析物的生物监测策略。在农作物上经常使用多种杀虫剂的农业中尤其如此。显然，有必要将这一战略扩展到其他重要的杀虫剂；然而，一个主要的限制是无法事先识别唾液中哪些化学物质容易被清除，这阻碍了我们轻松开发多重筛查平台的能力。为了应对这一挑战，假设可以很容易地预测一系列化学物质在唾液中的化学吸收和清除，这是基于有限的体外实验，并将其整合到药代动力学模型中。为了验证这一假设，这个继续项目将利用之前开发的唾液腺摄取和清除的在体大鼠模型，并将开发其他基于体外细胞和亚细胞的方法，用于具有不同物理和化学特性以及清除机制的广泛的杀虫剂。一旦得到验证，这种方法可以指导传感器平台的开发，因为模型模拟将提供有关检测极限和清除率的关键信息。

DESCRIPTION (provided by applicant): In articulating a vision for Toxicity Testing in the 21st Century, the National Research Council (NRC) noted that exposure science will play a critical role. In this context, biomonitoring is a key component that quantitatively associates an internal dose with a measurable effect. It has also been suggested that epidemiology studies which accurately assess chemical exposures along with biological effects will have the most meaningful interpretation and thus maximal impact. A major impediment for conducting biomonitoring within epidemiology studies is the lack of rapid, field deployable, quantitative technologies that measure chemical exposures using minimally invasive biological fluids, such as saliva. Our recently completed research resulted in the development of pesticide sensor platforms, an in vivo animal model system for rapid characterization of saliva pesticide uptake and clearance, and a dosimetry model to predict systemic dose based upon a 'spot' saliva measurement. Recently, the utility of the sensor was confirmed by measuring a target analyte in saliva from pesticide manufacturing plant workers. This project has been highly successful and can be utilized as a framework for evaluating a broader range of important chemicals. Since human exposure is rarely to single agents but rather to complex mixtures, there is a need to develop biomonitoring strategies capable of measuring multiple analytes. This is particularly true in agriculture where multiple pesticides are routinely utilized on crops. Clearly there is a need t extend the strategy to other important pesticides; however, a major limitation is the inability to priori identify which chemicals are readily cleared in saliva, hampering our ability to easily develop a multiplex screening platform. To address this challenge, it is hypothesized that chemical uptake and clearance in saliva can readily be predicted for a broad range of chemicals based upon limited in vitro experiments which are integrated into a pharmacokinetic model. To test this hypothesis this continuation project will exploit the previously developed in vivo rat model for salivary gland uptake and clearance and will develop additional in vitro cell and sub-cellular based approaches for a broad range of pesticides having differing physical and chemical characteristics as well as clearance mechanisms. Once validated, this approach can guide sensor platform development since model simulations will provide critical information on detection limits and clearance rates.