Nasal dosimetry of diacetyl and butyric acid vapors

描述（由申请人提供）：吸入材料的吸入毒性主要取决于其吸入剂量学模式；对于人造黄油调味剂产生的蒸汽来说尤其如此。虽然一般认为这些蒸汽与食品添加剂一样安全，但工人接触这些蒸汽与闭塞性细支气管炎有关。最近有研究表明，大鼠吸入黄油味蒸汽会导致鼻、支气管和细支气管气道坏死。暴露于二乙酰（2,3丁二烯），黄油调味蒸汽的主要成分，会导致鼻腔和气管坏死，但不会导致肺内气道坏死。二乙酰被二羰基还原酶代谢，二羰基还原酶是一种在人和啮齿动物呼吸组织中表达的酶。丁酸，黄油调味蒸汽的另一个主要成分，是二羰基还原酶的有效抑制剂。至于其他弱有机酸，丁酸很可能在上呼吸道有效沉积。已知鼻代谢可增强吸入代谢蒸气的吸收，抑制鼻代谢可减少该部位的吸收。这项小型拨款提案旨在表征上呼吸道对双乙酰的摄取，并测试共同暴露于丁酸蒸气导致上呼吸道摄取减少和激发双乙酰渗透到目标部位-下气道的假设。为了达到这些目的，我们将在手术分离的麻醉大鼠上呼吸道中以不同的吸入流速和吸入浓度测量双乙酰的摄取，并研究丁酸共暴露对鼻腔双乙酰摄取的影响，并评估丁酸体外抑制鼻腔双乙酰代谢的能力。拟议的研究将提供大量信息，这将显著提高我们定量评估与双乙酰/黄油调味蒸汽相关的风险的能力，但主要的健康意义在于利用这个例子来检验一种基于代谢的新型激发蒸汽-蒸汽相互作用机制。上呼吸道是一个具有代谢能力的器官，表达多种异种代谢系统；这种蒸汽-蒸汽相互作用机制可能与各种空气污染物有关。因此，从长远来看，拟议的研究有可能提高我们理解的能力，也许更重要的是，预测，在复杂的现实世界暴露情景中可能发生的毒理学相关的蒸汽-蒸汽相互作用。

DESCRIPTION (provided by applicant): The inhalation toxicity of inspired materials is critically dependent on their inhalation dosimetric patterns; this may be particularly true for the vapors derived from artificial butter flavorings. Although generally recognized as safe as food additives, exposure of workers to these vapors is associated with bronchiolitis obliterans. It has recently been shown that inhalation exposure of the rat to butter flavoring vapors results in necrosis of the nasal, bronchial and bronchiolar airways. Exposure to diacetyl (2,3 butadiene), a major component of butter flavoring vapors, results in necrosis of the nasal and trachea, but not the intrapulmonary airways. Diacetyl is metabolized by dicarbonyl reductase, an enzyme that is expressed in human and rodent respiratory tissues. Butyric acid, another major component of butter flavoring vapors, is a potent inhibitor of dicarbonyl reductase. As for other weak organic acids, it is likely that butyric acid deposits efficiently in the upper respiratory tract. Nasal metabolism is known to enhance uptake of inspired metabolized vapors, inhibition of nasal metabolism diminishes uptake in that site. This small grant proposal is aimed at characterizing upper respiratory tract uptake of diacetyl and testing the hypothesis that co-exposure to butyric acid vapor results in diminished upper respiratory tract uptake and enhanced penetration of inspired diacetyl to the target site- the lower airways. To achieve these aims uptake of diacetyl will be measured in the surgically isolated upper respiratory tract of the anesthetized rat at a variety of inspiratory flow rates and inspired concentrations, the effects of co-exposure to butyric acid on nasal diacetyl uptake will be examined, and the ability of butyric acid to inhibit nasal diacetyl metabolism in vitro will be assessed. The proposed research will provide much information that will significantly enhance our ability to quantitatively assess the risks associated with diacetyl/butter flavoring vapors, but the primary health significance lies in the use of this example to examine a novel metabolically-based mechanism for inspired vapor-vapor interactions. The URT is a metabolically competent organ expressing many xenobiotic metabolizing systems; such vapor-vapor interaction mechanisms could have relevance to a wide variety of air pollutants. Thus, in the long term, the proposed studies have the potential to enhance our ability to understand and perhaps more importantly, predict, toxicologically relevant vapor-vapor interactions that may occur during complex real world exposure scenarios.