Henderson R F, Pickrell J A, Jones R K, Sun J D, Benson J M, Mauderly J L, McClellan R O
Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185.
Fundam Appl Toxicol. 1988 Oct;11(3):546-67. doi: 10.1016/0272-0590(88)90119-4.
The effect of long-term (24 months) inhalation of diesel exhaust on the bronchoalveolar region of the respiratory tract of rodents was assessed by serial (every 6 months) analysis of bronchoalveolar lavage fluid (BALF) and of lung tissue from F344/Crl rats and CD-1 mice (both sexes) exposed to diesel exhaust diluted to contain 0, 0.35, 3.5, or 7.0 mg soot/m3. The purpose of the study was twofold. One was to assess the potential health effects of inhaling diluted exhaust from light-duty diesel engines. The second was to determine the usefulness of BALF analysis in detecting the early stages in the development of nononcogenic lung disease and differentiating them from the normal repair processes. No biochemical or cytological changes in BALF or in lung tissue were noted in either species exposed to the lowest, and most environmentally relevant, concentration of diesel exhaust. In the two higher levels of exposure, a chronic inflammatory response was measured in both species by dose-dependent increases in inflammatory cells, cytoplasmic and lysosomal enzymes, and protein in BALF. Histologically, after 1 year of exposure, the rats had developed focal areas of fibrosis associated with the deposits of soot, while the mice, despite a higher lung burden of soot than the rats, had only a fine fibrillar thickening of an occasional alveolar septa in the high-level exposure group. Higher increases in BALF beta-glucuronidase activity and in hydroxyproline content accompanied the greater degree of fibrosis in the rat. BALF levels of glutathione (GSH) and glutathione reductase activity increased in a dose-dependent fashion and were higher in mice than in rats. Lung tissue GSH was depleted in a dose-dependent fashion in rats but was slightly increased in mice. This depletion may have played a role in the greater fibrogenic response observed in rats. Other tissue changes in enzymatic activity were small compared to changes observed in BALF. The exposure did not increase the cytochrome P-450 content of the lung in either species. The results suggest that, for the noncarcinogenic health effects reported in this paper, there is a threshold of exposure below which adverse effects were not observed. This threshold was well above environmentally relevant levels of diesel exhaust but may be in the range of some occupational exposures. The analysis of BALF proved a useful adjunct to the chronic toxicity study to quantitate the inflammatory changes accompanying the development of pulmonary disease.
通过对暴露于稀释至含0、0.35、3.5或7.0毫克碳黑/立方米的柴油废气中的F344/Crl大鼠和CD-1小鼠（雌雄均有）的支气管肺泡灌洗液（BALF）和肺组织进行系列分析（每6个月一次），评估长期（24个月）吸入柴油废气对啮齿动物呼吸道支气管肺泡区域的影响。该研究目的有两个。一是评估吸入轻型柴油发动机稀释废气的潜在健康影响。二是确定BALF分析在检测非致癌性肺部疾病发展早期阶段并将其与正常修复过程区分开来方面的有用性。在暴露于最低且与环境最相关浓度柴油废气的两种物种中，未观察到BALF或肺组织有生化或细胞学变化。在两个较高暴露水平下，通过BALF中炎症细胞、细胞质和溶酶体酶以及蛋白质的剂量依赖性增加，在两种物种中均检测到慢性炎症反应。组织学上，暴露1年后，大鼠出现与碳黑沉积相关的局灶性纤维化区域，而小鼠尽管肺部碳黑负荷高于大鼠，但在高暴露组中仅偶尔有肺泡间隔的细微纤维增厚。大鼠中更高程度的纤维化伴随着BALF中β-葡萄糖醛酸酶活性和羟脯氨酸含量的更高增加。BALF中谷胱甘肽（GSH）水平和谷胱甘肽还原酶活性呈剂量依赖性增加，且小鼠中的水平高于大鼠。大鼠肺组织GSH呈剂量依赖性耗竭，但小鼠中略有增加。这种耗竭可能在大鼠中观察到的更大纤维化反应中起了作用。与在BALF中观察到的变化相比，其他组织中酶活性的变化较小。该暴露在两种物种中均未增加肺细胞色素P-450含量。结果表明，对于本文报道的非致癌健康影响，存在一个暴露阈值，低于该阈值未观察到不良反应。该阈值远高于与环境相关的柴油废气水平，但可能处于某些职业暴露范围内。BALF分析被证明是慢性毒性研究的有用辅助手段，可量化伴随肺部疾病发展的炎症变化。
