Bio-monitoring Methylene Diphenyl Diisocyanate (MDI) exposure and body burden

描述(由申请人提供)：接触异氰酸酯是制造聚氨酯的主要交联剂，是世界范围内职业性哮喘的主要原因。商业上主要使用三种类型的异氰酸酯，亚甲基二苯基二异氰酸酯(MDI)和甲苯二异氰酸酯(TDI)，或脂肪族六亚甲基二异氰酸酯(HDI)。尽管计量吸入器是三者中最新的，但由于许多原因，包括其独特的应用和特性，MDI在生产和消费方面已经超过了异氰酸酯市场。重要的是，在室温下，MDI的蒸气压比HDI或TDI低得多，而且是以固体而不是(挥发性)液体的形式存在。因此，计量吸入器被推定为“更安全”，因为呼吸道接触的可能性被认为仅限于化学物质被加热或雾化(喷洒)的时候，即在使用期间。MDI广泛用于制造软质和硬质泡沫塑料、涂料、弹性体和许多其他以聚氨酯为基础的产品。接触MDI是公认的MDI哮喘发展的最佳危险因素，减少暴露是疾病预防的主要策略。目前监测MDI暴露的方法受到严重限制，需要新的方法来帮助保护数百万在工作中暴露的人。在“生物监测亚甲基二苯基二异氰酸酯(MDI)暴露和身体负担”项目的第二阶段新申请中，我们的目标是开发创新的生物监测方法来监测MDI的暴露。调查小组由来自耶鲁大学医学院和小型企业L2诊断公司的科学家和医生组成，他们正在应用他们在免疫分析方面的专业知识来开发血液测试，以测量不同的MDI暴露生物标志物。其中一个生物标记物是MDI特异性抗体(IgG)，由免疫系统对暴露做出反应。第二个生物标记物是化学物质(MDI)本身，它与白蛋白结合，白蛋白是体内主要的“蛋白质加合物”。到目前为止，我们已经成功地完成了项目第一阶段的(4)个具体目标，并发表了支持性的发现(Wisnewski等人分析生物化学2010年；PMID：20123080)，包括关键试剂的生成及其广泛的表征。这些里程碑的完成表明我们准备着手该项目第二阶段的具体目标(如下所列)，这将导致用于生物监测MDI暴露的新的商业分析，这将有助于防止持续暴露和新的MDI哮喘病例。(目标1)确定两种新的实验室分析方法的分析性能特征，以测量MDI暴露的(生物标志物)。(目的2)确定新的MDI暴露(基于实验室)检测方法在暴露于MDI的工人和不同人群的对照非暴露个体中的临床敏感性。(目的3)利用新的MDI暴露试验，建立MDI免疫致敏的动力学，以及用于评估暴露工人的指征。

DESCRIPTION (provided by applicant): Exposure to isocyanate, the essential cross-linker for making polyurethane, is a leading cause of occupational asthma world-wide. Three major types of isocyanate are used commercially, methylene-diphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), or aliphatic, hexamethylene diisocyanate (HDI). Despite being the newest of the three, MDI has overtaken the isocyanate market in production and consumption, for many reasons, including its unique applications and properties. Importantly, at room temperature, MDI has a much lower vapor pressure than HDI or TDI, and exists as a solid, rather than a (volatile) liquid. Thus, MDI is presumed to be "safer", because the potential for respiratory tract exposure is thought to be restricted to times when the chemical is heated or aerosolized (sprayed), i.e. during application. MDI is widely used in making flexible and rigid foams, coatings, elastomers and numerous other polyurethane-based products. Exposure to MDI is the best-recognized risk factor for the development of MDI asthma and exposure reduction is the primary strategy of disease prevention. Contemporary methods of monitoring MDI exposure are severely limited, and new approaches are needed to help protect millions of people exposed at work. In this new phase II application for the project "Biomonitoring Methylene Diphenyl Diisocyanate (MDI) exposure and body burden", we aim to develop innovative biomonitoring approaches to exposure surveillance for MDI. The investigative team consists of scientists and physicians from Yale University School of Medicine and the small business, L2 Diagnostics, who are applying their expertise with immunoassays, to develop blood tests that measure (2) different MDI exposure biomarkers. One biomarker is MDI-specific antibodies (IgG), produced by the immune system in response to exposure. The second biomarker is the chemical (MDI) itself conjugated to albumin, the major "protein adduct" in vivo. To date, we have successfully completed the (4) Specific Aims of the projects 1st phase, and published supportive findings (Wisnewski et al Analytical Biochem 2010; PMID: 20123080), including the generation of key reagents, and their extensive characterization. Completion of these milestones demonstrates our readiness to embark on the specific aims of the project's 2nd phase (listed below), which should lead to new commercial assays for biomonitoring MDI exposure, which will help prevent ongoing exposures and new cases of MDI asthma. (Aim 1) Define the analytical performance characteristics of two new laboratory assays to measure (biomarkers of) MDI exposure. (Aim 2) Determine the clinical sensitivity of new MDI exposure (laboratory-based) assays, among MDI exposed workers and different populations of control unexposed individuals. (Aim 3) Using the new MDI exposure assays, establish the kinetics of MDI immune sensitization, and indications for use in evaluating exposed workers.