Non-Invasive Biological Monitoring of Pesticides

描述（由申请人提供）：在阐明21世纪世纪毒性试验的愿景时，国家研究理事会（NRC）指出，暴露科学将发挥关键作用。在这种情况下，生物监测是一个关键组成部分，定量地将内部剂量与可测量的影响联系起来。还有人建议，流行病学研究如果能准确评估化学品接触沿着生物效应，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快速、可现场部署的定量技术，这些技术可以使用侵入性最小的生物液体（如唾液）来测量化学品暴露。我们最近完成的研究导致农药传感器平台的发展，在体内动物模型系统的快速表征唾液农药的吸收和清除，和剂量测定模型，以预测全身剂量的基础上的“点”唾液测量。最近，该传感器的实用性通过测量来自农药制造厂工人的唾液中的目标分析物而得到证实。该项目非常成功，可用作评估更广泛的重要化学品的框架。由于人类接触很少是单一的代理，而是复杂的混合物，有必要开发能够测量多种分析物的生物监测策略。在农业中尤其如此，在农业中，多种农药通常用于作物。显然，有必要将该策略扩展到其他重要的农药;然而，一个主要的限制是无法事先确定哪些化学物质容易在唾液中清除，这阻碍了我们轻松开发多重筛选平台的能力。为了解决这一挑战，假设可以基于整合到药代动力学模型中的有限体外实验，针对广泛的化学品容易地预测唾液中的化学品摄取和清除。为了验证这一假设，该延续项目将利用先前开发的唾液腺摄取和清除的体内大鼠模型，并将为具有不同物理和化学特性以及清除机制的广泛农药开发额外的体外细胞和亚细胞方法。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.