Evaluation of urinary 1-nitropyrene metabolities as a biomarker for exposure to d

描述(由申请人提供)：柴油废气(DE)是环境细颗粒物空气污染(PM)的主要来源，并与急性和慢性健康影响有关。随着人们对柴油废气对健康危害的认识日益加深，监管机构已作出回应，提议并执行对工作场所和周围环境中的柴油许可排放量和DE水平施加更严格的限制。发动机技术的进步意味着柴油发动机的污染比过去低了一个数量级。尽管在减少柴油排放方面进行了大量的经济投资，但目前尚不清楚这些干预措施是否大幅减少了个人对DE的暴露，或改善了公共卫生。由于暴露评估方法不充分，调查DE暴露与不良健康影响之间的关系受到阻碍。这些限制包括：DE缺乏特异性，个人和中央监视器暴露指标之间的相关性较差，无法考虑个人防护装备或行为对个人暴露的修改影响，以及未能捕捉到个人暴露与吸收剂量的差异。硝基-多环芳烃，1-硝基并(1-NP)被认为是唯一的DE标志物，可以用来定量DE对环境PM的贡献我们的假设是，人体尿样中1-硝基吡喃代谢物的测定可以作为DE暴露的生物标志物。我们的主要假设是，人类暴露在柴油尾气中会导致尿中1-硝基吡喃(1-NP)代谢物的排泄呈剂量依赖性增加，这将是一个合适的暴露生物标志物的基础。为了验证这一假设，我们提出了以下具体目标：(1)建立灵敏的GC/NICI/MS方法来测定人尿中的1-硝基吡喃代谢物。(2)探讨职业和环境中柴油车尾气暴露人群尿中1-硝基吡喃代谢物排泄的剂量-反应关系。(3)我们将调查受试者内和受试者之间尿中1-硝基吡喃代谢物排泄的差异。这些研究将提供原理证据，证明人体尿液中的1-硝基吡喃代谢物浓度是暴露于DE的有用生物标记物。DE暴露的生物标记物对于准确评估个体暴露于DE及其剂量将是重要的。生物标记物将有助于评估旨在减少DE暴露的法规和技术干预措施的有效性，并可用于流行病学调查，以确定DE排放量的减少是否与公共卫生的改善有关。

DESCRIPTION (provided by applicant): Diesel exhaust (DE) represents a major source of ambient fine particulate matter air pollution (PM), and has been associated with both acute and chronic health effects. As recognition of the health hazards of diesel exhaust has increased, regulatory bodies have responded by proposing and enforcing ever-more stringent limits on permissible diesel emissions and levels of DE in workplaces and in the ambient environment. Advancements in engine technology mean that diesel engines are up to an order of magnitude less polluting than in the past. In spite of the large economic investment in reducing diesel emissions, it remains unclear whether these interventions have substantially reduced personal exposures to DE, or improved public health. Investigating the relationship between DE exposure and adverse health effects is hindered by inadequate methods of exposure assessment. These limitations include: lack of specificity for DE, poor correlation between personal and central monitor exposure metrics, inability to account for modifying effect of personal protective equipment or behavior on personal exposures, and failure to capture differences in personal exposure versus absorbed dose. The nitro-PAH, 1-nitropyrene (1-NP) has been proposed as a unique marker for DE, and can be used to quantify the contribution of DE to ambient PM. It is our hypothesis that measurements of 1-nitropyrene metabolites in human urine samples could be used as a biomarker of exposure to DE. Our primary hypothesis is that human exposure to diesel exhaust results in a dose-dependent increase in urinary excretion of 1-nitropyrene (1-NP) metabolites that would be a suitable basis for a biomarker of exposure. To evaluate this hypothesis we propose the following specific aims (1) Develop sensitive GC/NICI/MS methods for the determination of 1-nitropyrene metabolites in human urine. (2) Investigate the dose-response relationship for urinary 1-nitropyrene metabolite excretion in individuals with elevated occupational and environmental exposures to diesel exhaust. (3) We will investigate within and between subject variation in urinary excretion of 1-nitropyrene metabolites. These studies will provide proof-of-principle that 1-nitropyrene metabolite concentrations in human urine are useful biomarkers of exposure to DE. A biomarker of DE exposure will be important to accurately assess individual exposure to and dose from DE. The biomarker will be useful to assess the effectiveness of regulations and technical interventions designed to reduce DE exposures, and can be used in epidemiological investigations to determine whether reduction in DE emissions are associated with improvements in public health.