New Serodiagnostics for Isocyanate Exposure, A Major Cause of Occupational Asthma

描述（由申请人提供）：职业暴露估计占成人哮喘病例的9-15%。职业性哮喘最常见的原因是异氰酸酯，这是制造聚氨酯产品（建筑、汽车、军事、医疗、泡沫、涂料、粘合剂）所必需的反应性化学品。目前有数百万人从事使用异氰酸酯的行业，随着消费者对聚氨酯的需求不断增加，面临暴露风险的劳动力也在不断增加。识别和诊断异氰酸酯哮喘对患者和医生都具有挑战性。症状可能是潜伏的，很难与工作场所联系起来，尤其是反应迟缓，通常被错误地归因于环境触发因素。对异氰酸酯产生免疫超敏反应的工人，可能出现长期的肺功能下降，并在停止接触后持续数年。暴露是唯一已知的异氰酸酯哮喘的危险因素，也是疾病预防的主要目标。现代工业卫生技术（呼吸器，“喷雾室”）减少，但不能消除工作场所的暴露。据估计，在职业暴露者中，仍有5 - 10%的人出现异氰酸酯哮喘新病例，这是一个重大的公共卫生问题。尽管异氰酸酯具有众所周知的致敏性，但职业暴露评估和疾病筛查是有限的。临床实践和工作场所筛查非常需要可靠地区分对异氰酸酯和其他哮喘诱因敏感性的诊断分析。还需要异氰酸酯暴露的生物标志物来帮助指导和监测工业卫生工作。我们假设异氰酸酯血清学检测可以发展为疾病监测和工业卫生（暴露）监测的策略，以帮助保护职业暴露于异氰酸酯的个体。该项目开发的血清诊断在两个主要方面是新的。(1)它们将基于新型“异氰酸酯抗原”，使用我们实验室开发的混合相（蒸汽/气溶胶/液体）暴露系统生产，该系统模拟了人类气道内支气管液体的空气/液体界面。(2)他们将利用过敏生物标志物（IgE）来检测过敏个体，并利用异氰酸酯暴露免疫标志物（IgG）来帮助定位和监测工业卫生工作。该项目的最终产品将是一个敏感和特异的酶联免疫吸附试验试剂盒，结合这些独特的品质，这将对临床医生、研究科学家、工业管理和卫生保健提供者具有广泛的价值。我们实验室发表的研究结果预测，ELISA试剂盒将远远优于目前市场上仅有的1种类似产品（由单一供应商主导市场），并将消除可能从先前使用可疑生物相关性异氰酸酯抗原的研究中得出的错误结论。公共卫生相关性：本资助申请的重点是更好地了解异氰酸酯的致敏性，异氰酸酯是世界范围内职业性哮喘的主要原因。该研究的预期产品将是一种基于新型异氰酸酯-蛋白质复合物的血清诊断分析，可用于通过(1)识别超敏感工人，(2)识别工作场所的暴露热点，(3)监测内部暴露，(4)监测工业卫生工作的有效性来保护工人健康。

DESCRIPTION (provided by applicant): Occupational exposures are estimated to account for 9-15% of adult asthma cases. Among the most common causes of occupational asthma are isocyanates, reactive chemicals necessary to make polyurethane products (construction, automotive, military, medical, foam, coatings, adhesives). Millions of people are currently employed in industries that utilize isocyanates, and the work-force at risk for exposure continues to grow along with consumer demand for polyurethane. Recognition and diagnosis of isocyanate asthma can be challenging for both patients and physicians. Symptoms can be insidious and difficult to associate with the workplace, especially delayed responses, which are often mistakenly attributed to environmental triggers. In workers that develop immunologic hypersensitivity to isocyanate, long-lasting decrements in lung function may occur, and persist years after exposure ceases. Exposure is the only known risk factor for isocyanate asthma, and is the major target for disease prevention. Contemporary industrial hygiene technologies (respirators, "spray booths") reduce, but cannot eliminate workplace exposure. New cases of isocyanate asthma continue to occur in an estimated 5 - 10 % of those occupationally exposed, and represent a substantial public health problem. Despite the well-known allergenicity of isocyanates, occupational exposure assessment and disease screening is limited. Diagnostic assays that reliably differentiate sensitivity to isocyanate vs other asthma triggers are greatly needed for clinical practice as well as workplace screening. Biomarkers of isocyanate exposure are also needed to help guide and monitor industrial hygiene efforts. We hypothesize that isocyanate serology assays can be developed as a strategy for disease surveillance and industrial hygiene (exposure) monitoring to help protect individuals who are occupationally exposed to isocyanate. The serodiagnostics that would be developed in this project are new in two major ways. (1) They would be based upon novel "isocyanate antigens", produced using a mixed phase (vapor/aerosol/liquid) exposure system developed by our laboratory, which mimics the air/liquid interface of the bronchial fluid that lines human airways. (2) They would utilize biomarkers of allergy (IgE) to detect hypersensitive individuals, AND make use of immunologic markers of isocyanate exposure (IgG), to help target and monitor industrial hygiene efforts. The final product of this project would be a sensitive and specific ELISA kit, incorporating these unique qualities, which would have widespread value for clinicians, research scientists, industrial management and health care providers. Published findings from our laboratory predict the ELISA kit will be far superior to the only 1 other similar product currently available commercially (by a single supplier that dominates the market), and will dispel false conclusions that may have been drawn from previous studies using isocyanate antigens of questionable biologic relevance. PUBLIC HEALTH RELEVANCE: This grant application focuses on developing a better understanding the allergenicity of isocyanates, a major cause of occupational asthma world-wide. The expected product of the study will be a serodiagnostic assay, based upon novel isocyanate-protein complexes, that can be used to protect workers health by (1) identifying hypersensitive workers, (2) identifying exposure hot spots in the workplace (3) monitoring internal exposure and (4) monitoring the effectiveness of industrial hygiene efforts.