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

描述（由申请人提供）：柴油机排气（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。随着人们对柴油机废气健康危害的认识不断提高，监管机构已做出回应，对工作场所和周围环境中的柴油机排放和DE水平提出并实施了更严格的限制。发动机技术的进步意味着柴油发动机的污染比过去减少了一个数量级。尽管在减少柴油机排放方面进行了大量的经济投资，但尚不清楚这些干预措施是否大幅减少了个人对DE的暴露，或改善了公众健康。由于暴露评估方法不足，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，个人和中央监测器暴露度量之间相关性差，无法解释个人防护设备或行为对个人暴露的修改效果，以及无法捕获个人暴露与吸收剂量的差异。1-硝基芘（1-NP）是DE的一种独特的标记物，可用于定量DE对环境PM的贡献。我们的假设是，人尿液样本中1-硝基芘代谢物的测量值可用作DE暴露的生物标志物。我们的主要假设是，人体暴露于柴油机废气导致1-硝基芘（1-NP）代谢物的尿排泄量呈剂量依赖性增加，这将是一个合适的基础暴露的生物标志物。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方法测定人尿中的1-硝基芘代谢物。(2)研究职业和环境暴露于柴油机废气的个体尿1-硝基芘代谢物排泄的剂量-反应关系。(3)我们将研究1-硝基芘代谢物尿排泄的受试者内和受试者之间的变化。这些研究将提供原理证明，即人尿液中的1-硝基芘代谢物浓度是暴露于DE的有用生物标志物。DE暴露的生物标志物对于准确评估DE的个体暴露和剂量非常重要。生物标志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.