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

描述（由申请人提供）：暴露于异氰酸酯（制造聚氨酯的基本交联剂）是全球职业性哮喘的主要原因。三种主要类型的异氰酸酯在商业上使用，亚甲基二苯基二异氰酸酯（MDI）和甲苯二异氰酸酯（TDI），或脂肪族二异氰酸酯（HDI）。尽管MDI是三种产品中最新的一种，但由于其独特的应用和性能等原因，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，并且以固体而不是（挥发性）液体存在。因此，计量吸入器被认为是“更安全的”，因为呼吸道接触的可能性被认为仅限于化学品加热或雾化（喷雾）的时间，即在使用过程中。 MDI广泛用于制造软质和硬质泡沫、涂料、弹性体和许多其他基于聚氨酯的产品。暴露于MDI是最公认的MDI哮喘发展的危险因素，减少暴露是疾病预防的主要策略。监测计量吸入器接触的现代方法受到严重限制，需要新的方法来帮助保护数百万在工作中接触的人。 在“生物监测亚甲基二苯基二异氰酸酯（MDI）暴露和身体负荷”项目的第二阶段新申请中，我们的目标是开发创新的MDI暴露监测生物监测方法。调查小组由来自耶鲁大学医学院和小企业L2 Diagnostics的科学家和医生组成，他们正在运用他们在免疫测定方面的专业知识，开发测量（2）不同MDI暴露生物标志物的血液测试。一种生物标志物是MDI特异性抗体（IgG），由免疫系统对暴露做出反应。第二种生物标志物是与白蛋白结合的化学物质（MDI）本身，白蛋白是体内主要的“蛋白加合物”。到目前为止，我们已经成功完成了项目第一阶段的（4）特定目标，并发表了支持性发现（Wisnewski et al Analytical Biochem 2010; PMID：20123080），包括关键试剂的生成及其广泛表征。这些里程碑的完成表明我们已经准备好开始项目第二阶段的具体目标（如下所列），这将导致新的商业测定用于生物监测MDI暴露，这将有助于防止持续的暴露和MDI哮喘的新病例。(Aim 1）确定两种新的实验室测定方法的分析性能特征，以测量MDI暴露（的生物标志物）。(Aim 2）确定新的MDI暴露（基于实验室的）检测方法在MDI暴露工人和不同人群的对照未暴露个体中的临床敏感性。(Aim 3）使用新的MDI暴露测定法，建立MDI免疫致敏的动力学，以及用于评估暴露工人的适应症。 公共卫生相关性：该申请将开发两种新的免疫测定法，以生物监测工作场所的MDI暴露，从而确保聚氨酯生产的充分安全，并保护美国劳动力的健康。

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. PUBLIC HEALTH RELEVANCE: This application will develop two new immunoassays to bio-monitor MDI exposure in the workplace thus, ensuring adequate safety in polyurethane manufacture, and protecting the health of the US workforce.