Gallagher J E, Jackson M A, George M H, Lewtas J
Genetic Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC 27711.
Carcinogenesis. 1990 Jan;11(1):63-8. doi: 10.1093/carcin/11.1.63.
Dose-related differences in the binding of DNA reactive intermediates for three environmentally important complex mixture particulate extracts and a well-studied carcinogen, benzo[a]pyrene (BaP), were examined in female C-57 mice following multiple topical treatments ranging from 1 to 120 mg/mouse. Particulate extracts from coke oven, coal soot and diesel exhaust were selected as model complex mixtures based on short-term mutagenicity assays, animal bioassays for carcinogenicity or epidemiological studies, where increased incidences of lung cancer in exposed populations were detected. Positive and negative control animals were treated with 1.2 mg BaP or acetone respectively. DNA was isolated from skin, lung and liver 24 h following the last application and analyzed for DNA adducts using the nuclease P1 version of the 32P-postlabeling assay. Each of the particulate extracts produced distinct patterns of DNA adducts. A diagonal zone of radioactivity, presumably representing multiple putative DNA adducts, was observed for coke-oven, coal-soot- and diesel-modified DNA samples. One adduct, common to all three complex-mixture-modified DNA samples, co-migrated with the major BaP adduct observed following treatment with BaP alone. Based on the BaP concentration for each of the extracts it seems unlikely that this adduct is derived from BaP alone. It is possible that an adduct is formed with chromatographic properties similar to the major BaP-derived adduct detected in mice treated with BaP alone. This adduct was detected in all tissues examined and represented approximately 12-34% of the total number of adducts detected within the diagonal radioactive zone for all coke-oven- and coal-soot-exposed tissues (skin, lung and liver). In contrast, this adduct represented 49-67% of the total radioactivity recovered from the diagonal zone of DNA isolated from lungs of animals exposed to diesel extract. The highest total number of adducts resulted from the metabolism of coke oven extract followed by coal soot and diesel treatments respectively. A dose-dependent increase in adduct formation was observed for all tissues in the diesel- and coal-soot-treatment mice. Liver and lung, but not skin, DNA adduct levels increased in a dose-dependent manner in the coke-oven-treated mice. The percentage of dose administered, detected as DNA adducts increased in all tissues as the dose decreased for all three complex mixtures. These data have important implications for risk assessment of these complex mixtures.
在雌性C-57小鼠中，在1至120毫克/小鼠的多次局部处理后，检测了三种对环境重要的复杂混合物颗粒提取物以及一种经过充分研究的致癌物苯并[a]芘（BaP）与DNA反应性中间体结合的剂量相关差异。基于短期致突变性试验、致癌性动物生物测定或流行病学研究，选择焦炉、煤烟和柴油废气的颗粒提取物作为模型复杂混合物，在这些研究中检测到暴露人群肺癌发病率增加。阳性和阴性对照动物分别用1.2毫克BaP或丙酮处理。在最后一次应用后24小时从皮肤、肺和肝脏中分离DNA，并使用32P后标记测定法的核酸酶P1版本分析DNA加合物。每种颗粒提取物都产生了不同的DNA加合物模式。在焦炉、煤烟和柴油修饰的DNA样品中观察到一个放射性对角线区域，可能代表多种假定的DNA加合物。所有三种复杂混合物修饰的DNA样品共有的一种加合物，与单独用BaP处理后观察到的主要BaP加合物一起迁移。根据每种提取物的BaP浓度，这种加合物似乎不太可能仅来自BaP。有可能形成一种加合物，其色谱性质与单独用BaP处理的小鼠中检测到的主要BaP衍生加合物相似。在所有检查的组织中都检测到了这种加合物，在所有暴露于焦炉和煤烟的组织（皮肤、肺和肝脏）的对角线放射性区域内检测到的加合物总数中，这种加合物约占12 - 34%。相比之下，这种加合物占从暴露于柴油提取物的动物肺部分离的DNA对角线区域回收的总放射性的49 - 67%。加合物总数最高的是焦炉提取物的代谢产物，其次是煤烟和柴油处理产物。在柴油和煤烟处理的小鼠中，所有组织中加合物形成均呈现剂量依赖性增加。在焦炉处理的小鼠中，肝脏和肺（而非皮肤）的DNA加合物水平呈剂量依赖性增加。随着所有三种复杂混合物剂量的降低，作为DNA加合物检测到的给药剂量百分比在所有组织中均增加。这些数据对这些复杂混合物的风险评估具有重要意义。
