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，并且与急性和慢性健康影响有关。随着人们越来越认识到柴油废气对健康的危害，监管机构对此作出了回应，提出并实施了越来越严格的柴油排放限值，以及工作场所和环境中的DE水平。发动机技术的进步意味着柴油发动机的污染比过去少了一个数量级。尽管在减少柴油排放方面进行了大量经济投资，但尚不清楚这些干预措施是否大大减少了个人对DE的暴露，或改善了公众健康。暴露评估方法的不完善阻碍了对DE暴露与不良健康影响之间关系的调查。这些限制包括：缺乏DE的特异性，个人和中央监护仪暴露指标之间的相关性较差，无法解释个人防护设备或行为对个人暴露的改变作用，以及未能捕获个人暴露与吸收剂量的差异。硝基多环芳烃，1-硝基芘（1-NP）已被提出作为DE的独特标记物，可用于量化DE对环境PM的贡献。我们的假设是，人类尿液样本中1-硝基芘代谢物的测量可以用作DE暴露的生物标志物。我们的主要假设是，人类暴露于柴油废气中会导致尿中1-硝基芘（1-NP）代谢物的剂量依赖性增加，这将是暴露的生物标志物的合适基础。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方法来测定人类尿液中的1-硝基芘代谢物。(2)研究柴油机废气职业和环境暴露增高人群尿1-硝基芘代谢物排泄的量效关系。(3)我们将研究受试者尿中1-硝基芘代谢物排泄的内部和之间的差异。这些研究将提供原理证明，即人类尿液中1-硝基芘代谢物浓度是有效的DE暴露生物标志物。DE暴露生物标志物对于准确评估个体暴露和DE暴露剂量非常重要。该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，以确定减少DE排放是否与改善公共卫生有关。

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.