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。我们的实验室目前正在研究基于血清生物标记物的MDI暴露监测的新方法，这比(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来量化两个生物标记物，我们假设这两个生物标记物提供了重要的MDI暴露信息，这可以极大地改善当前的监测计划。其中一个生物标志物是MDI特异性免疫球蛋白，根据我们在背景中概述的原则(B部分)，它应作为有效的暴露替代品，并可通过间接酶联免疫吸附试验(ELISA)进行测量。第二个生物标记物是MDI本身，它在外周血液中循环附着到自身蛋白质上，我们建议用一种“三明治”式的ELISA法来“捕捉”它。我们的愿景是将这些血清生物标记物及其定量的免疫分析方法成为综合多学科MDI暴露监测计划的一部分，以帮助保护世界各地数百万工人的健康。研究人员以前的经验和迄今获得的初步数据将促进拟议免疫分析的发展。该项目的具体目标如下：目标1)制备和鉴定候选MDI(结合白蛋白)抗原。目的2)建立检测MDI特异性抗体(Biomarker 1)的方法。目的3)制备并鉴定(兔)MDI多克隆抗体和(小鼠)MDI单抗。目的4)建立检测和定量人血清中MDI的免疫分析方法(生物标志物2)。 与公共健康相关：这一应用程序将开发两种新的免疫分析方法，以生物监测工作场所的MDI暴露，从而确保聚氨酯制造过程中的足够安全，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. 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.