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。我们的实验室目前正在研究基于血清生物标志物的MDI暴露监测的新方法，它比（工作场所）环境监测具有明显的优势。我们的新方法使用免疫分析法来量化两种生物标志物，我们假设这两种生物标志物提供了重要的MDI暴露信息，这可以极大地改善当前的监测计划。一种生物标志物是mdi特异性IgG，根据我们在背景（B节）中概述的原则，它可以作为有效的暴露替代物，并且可以通过间接酶联免疫吸附试验（ELISA）进行测量。第二个生物标志物是MDI本身，它在外周血中循环，附着在自身蛋白上，我们建议用“三明治”型ELISA“捕获”MDI。我们的愿景是将这些血清生物标记物及其定量免疫测定法纳入多学科MDI暴露综合监测计划，帮助保护全世界数百万工人的健康。研究人员以往的经验和迄今获得的初步数据将促进拟议免疫测定的发展。该项目的具体目的如下：目的1)产生和表征候选MDI（偶联白蛋白）抗原。目标2)开发测量mdi特异性抗体（生物标志物1）的方法。目的3)制备和鉴定（兔）多克隆和（小鼠）单克隆mdi特异性抗体。目标4)发展检测和定量人血清中MDI（生物标志物2）的免疫测定法。

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. Our laboratory is currently investigating new approaches to MDI exposure surveillance based upon serum biomarkers, which offer distinct advantages over (workplace) environmental surveillance. Our new approach uses immunoassays to quantitate two biomarkers we hypothesize provide important MDI exposure information and, which can greatly improve current surveillance programs. One biomarker is MDI-specific IgG, which should serve as an effective exposure surrogate, according to principles we outline in the Background (Section B), and can be measured through an indirect enzyme-linked immunosorbant assays (ELISA). A second biomarker is MDI itself, circulating in the peripheral blood attached to self proteins, which we propose to "capture" in a "sandwich"-type ELISA. Our vision is for these serum biomarkers, and immunoassays for their quantitation, to become part of integrated multi-disciplinary MDI exposure monitoring programs, which help protect the health of millions of workers throughout the world. Development of the proposed immunoassays will be facilitated by previous experience of the research personnel, and preliminary data acquired to date. The Specific Aims of the project are the following: Aim 1) Generate and characterize candidate MDI (conjugated albumin) antigens. Aim 2) Develop methods to measure MDI-specific antibodies (biomarker 1). Aim 3) Generate and characterize (rabbit) polyclonal and (mouse) monoclonal MDI-specific antibodies. Aim 4) Develop immunoassays that detect and quantitate MDI in human serum (biomarker 2). 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.