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

生物监测亚甲基二苯基二异氰酸酯 (MDI) 暴露和身体负担

• 批准号: 8124388
• 负责人: ADAM WISNEWSKI
• 金额: $ 73.66万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124388
• 关键词: Albumins; Antibodies; Antigens; Asthma; Biological; Biological Assay; Biological Markers; Biological Monitoring; Blood; Blood Tests; Body Burden; Businesses; Calibration; Characteristics; Chemicals; Clinical; Clinical Sensitivity; Coagulants; Collection; Consumption; Development; Diagnostic; Disease; Elastomers; Ensure; Exposure to; Fingers; Generations; Health; Heating; Human; Immune; Immune Sera; Immune system; Immunoassay; Immunoglobulin G; Individual; Isocyanates; Kinetics; Laboratories; Lead; Life; Liquid substance; Marketing; Measures; Methods; Monitor; Occupational Asthma; Performance; Pharmaceutical Preparations; Phase; Physicians; Polyurethanes; Population Control; Predictive Value; Production; Property; Proteins; Publishing; Readiness; Reagent; Respiratory System; Respiratory tract structure; Risk Factors; Safety; Sampling; Scientist; Serum; Solid; Specificity; Temperature; Time; Toluene Diisocyanate; Universities; Venipunctures; Work; Workplace; adduct; aerosolized; base; carbene; diphenyl; disorder prevention; flexibility; in vivo; innovation; medical schools; novel strategies; pressure; prevent; response; vapor

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.

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）是世界范围内职业性哮喘的主要原因。商业上使用的三种主要类型的异氰酸酯，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MDI是三者中最新的一种，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的蒸汽压比HDI或TDI低得多，并且以固体而不是（挥发性）液体的形式存在。因此，MDI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（喷洒）时，即在使用期间。MDI广泛用于制造柔性和刚性泡沫、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哮喘发生的危险因素，减少暴露是疾病预防的主要策略。监测MDI暴露的现代方法严重有限，需要新的方法来帮助保护数百万在工作中暴露的人。在这个新的二期申请项目“亚甲基二苯基二异氰酸酯（MDI）暴露和身体负担的生物监测”中，我们的目标是开发创新的MDI暴露监测的生物监测方法。调查小组由来自耶鲁大学医学院和小型企业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，开发出测量(2)种不同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），由免疫系统在暴露后产生。第二个生物标志物是化学物质（MDI）本身与白蛋白结合，白蛋白是体内主要的“蛋白质加合物”。到目前为止，我们已经成功完成了项目第一阶段的具体目标，并发表了支持性研究结果（Wisnewski et al Analytical Biochem 2010; 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已经准备好着手实现该项目第二阶段的具体目标（如下所列），这将导致用于MDI暴露生物监测的新的商业分析，这将有助于预防持续暴露和MDI哮喘的新病例。（目标1）定义两种新的实验室检测方法的分析性能特征，以测量MDI暴露（生物标志物）。（目的2）确定MDI暴露工人和不同对照未暴露人群中MDI新暴露（基于实验室的）检测的临床敏感性。（目标3）使用新的MDI暴露试验，建立MDI免疫致敏动力学，以及用于评估暴露工人的适应症。