Mauderly J L, Snipes M B, Barr E B, Belinsky S A, Bond J A, Brooks A L, Chang I Y, Cheng Y S, Gillett N A, Griffith W C
Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM.
Res Rep Health Eff Inst. 1994 Oct(68 Pt 1):1-75; discussion 77-97.
This study compared the pulmonary carcinogenicities and selected noncancer effects produced by chronic exposure of rats at high rates to diesel exhaust and carbon black. The comparison was intended to provide insight into the likely importance of the mutagenic organic compounds associated with the soot portion of diesel exhaust in inducing pulmonary carcinogenicity in diesel exhaust-exposed rats. The role of the organic fraction has become important in judging the usefulness of the substantial data base on carcinogenicity in rats for predicting lung cancer risk for humans, and for determining the most appropriate method of extrapolating results across species and exposure concentrations. Rats were exposed chronically to either diesel exhaust or carbon black, which served as a surrogate for diesel exhaust soot with much reduced mutagenic activity associated with its organic fraction. The sequestration of particles in the lung and the induction of pulmonary neoplasia and non-neoplastic changes in the lung were compared in detail. Samples also were provided to collaborators to examine adduct formation in lung DNA and hemoglobin. Approximately 140 female and 140 male F344/N rats were exposed for 16 hours per day, 5 days per week for up to 24 months, beginning at eight weeks of age, to diesel exhaust or carbon black at 2.5 mg or at 6.5 mg particles/m3 of air, or to clean air as controls. The diesel exhaust was generated by light-duty engines burning certification fuel and operating on an urban-duty cycle. The carbon black was selected because it had particle size and surface area characteristics similar to those of diesel exhaust soot, but markedly less mutagenic activity associated with its organic fraction when analyzed using procedures typically used in studies of diesel soot. Rats were killed after 3, 6, 12, 18, or 23 months of exposure to measure lung and lung-associated lymph node burdens of particles, lung weight, bronchoalveolar lavage indicators of inflammation, DNA adducts in whole lung and alveolar type II cells, and chromosome injury in circulating lymphocytes, and to perform histopathologic assessment. In addition, after 3 and 18 months of chronic exposure, one group of rats was acutely exposed to radiolabeled carbon black particles or to fluorescent microspheres. These exposures were conducted to examine the clearance of radiolabeled particles and the sequestration of the fluorescent microspheres in the lungs. These experiments provided information on clearance overload and particle dosimetry. The growth characteristics of lung neoplasms also were examined by transplanting neoplastic cells into athymic mice.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究比较了大鼠长期高剂量暴露于柴油机尾气和炭黑所产生的肺致癌性及某些非致癌效应。该比较旨在深入了解与柴油机尾气烟灰部分相关的致突变有机化合物在诱发暴露于柴油机尾气的大鼠肺致癌性方面可能的重要性。有机成分的作用在判断基于大鼠致癌性的大量数据库对预测人类肺癌风险的有用性，以及确定跨物种和暴露浓度外推结果的最合适方法时变得至关重要。大鼠被长期暴露于柴油机尾气或炭黑，炭黑用作柴油机尾气烟灰的替代物，其有机成分的致突变活性大幅降低。详细比较了肺部颗粒的滞留情况以及肺部肿瘤形成和非肿瘤性变化的诱导情况。还向合作者提供样本，以检查肺DNA和血红蛋白中的加合物形成。约140只雌性和140只雄性F344/N大鼠从8周龄开始，每天暴露16小时，每周5天，持续长达24个月，暴露于浓度为2.5毫克或6.5毫克颗粒/立方米空气的柴油机尾气或炭黑，或作为对照暴露于清洁空气中。柴油机尾气由燃烧认证燃料并按城市工况运行的轻型发动机产生。选择炭黑是因为其粒径和表面积特征与柴油机尾气烟灰相似，但使用柴油机烟灰研究中常用的程序分析时，其有机成分的致突变活性明显较低。在暴露3、6、12、18或23个月后处死大鼠，以测量肺部和与肺相关的淋巴结颗粒负荷、肺重量、支气管肺泡灌洗炎症指标、全肺和II型肺泡细胞中的DNA加合物以及循环淋巴细胞中的染色体损伤，并进行组织病理学评估。此外，在慢性暴露3个月和18个月后，一组大鼠被急性暴露于放射性标记的炭黑颗粒或荧光微球。进行这些暴露是为了检查放射性标记颗粒的清除情况以及荧光微球在肺部的滞留情况。这些实验提供了关于清除超载和颗粒剂量测定的信息。还通过将肿瘤细胞移植到无胸腺小鼠中来检查肺肿瘤的生长特征。（摘要截取自400字）
