Jansson T, Romert L, Magnusson J, Jenssen D
Genotox AB, Stockholm, Sweden.
Mutat Res. 1991 Oct;261(2):101-15. doi: 10.1016/0165-1218(91)90056-r.
The present study was designed to investigate the potential genotoxicity of aqueous and methylene chloride extracts of Swedish moist oral snuff. The test systems were selected to provide optimal data for the prediction of carcinogenicity in rodents and included assays for the induction of mutation in bacteria, sister-chromatid exchanges (SCE) in human lymphocytes, of chromosome aberrations and gene mutations in V79 Chinese hamster cells and of micronuclei in mouse bone marrow cells. In addition, the methylene chloride extract was tested for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster. The aqueous extract of 'Snus' induced SCE in human lymphocytes and chromosome aberrations in V79 cells, the latter effect being observed both with and without metabolic activation. No induction of point mutations was detected with the Ames test or in V79 cells and the micronucleus test in mice was negative. It was demonstrated that the induction of chromosome aberrations without metabolic activation may be due to a high salt concentration, indicating that the clastogenic agent(s) in this extract required metabolic activation. The methylene chloride extract showed genotoxicity in the Ames test, the SCE test and the chromosome aberration test, whereas no induction of gene mutations in V79 cells was observed. Once again, the results suggested that metabolism is required for genotoxicity. The methylene chloride extract did not cause induction of micronuclei in mice or of sex-linked recessive lethal mutations in Drosophila melanogaster. These combined data on genotoxicity were analyzed using various models for the prediction of carcinogenicity. In a sequential testing model, the probabilities that the aqueous and methylene chloride extracts of 'Snus' are carcinogenic due to a genotoxic mechanism were both predicted to be low. Using carcinogenicity prediction by battery selection (CPBS), the probabilities of the methylene chloride and aqueous extracts being correctly identified as non-carcinogens are 71 and 77%, respectively. Up to date, the CPBS approach has been validated primarily for individual compounds, so some caution should at present be exercised in interpreting the results using this method. Based on these results, the carcinogenic potential of Swedish 'Snus' should be considered to be low, a conclusion in agreement with the low incidence of oral cancer in Sweden compared to other countries.
本研究旨在调查瑞典湿鼻烟的水提取物和二氯甲烷提取物的潜在遗传毒性。所选用的测试系统是为了提供预测啮齿动物致癌性的最佳数据，包括细菌诱变性检测、人淋巴细胞姐妹染色单体交换（SCE）检测、V79中国仓鼠细胞染色体畸变和基因突变检测以及小鼠骨髓细胞微核检测。此外，还对二氯甲烷提取物进行了黑腹果蝇性连锁隐性致死突变诱导试验。“鼻烟”的水提取物可诱导人淋巴细胞发生SCE，并在V79细胞中诱导染色体畸变，无论有无代谢活化均能观察到后一种效应。在Ames试验或V79细胞中未检测到点突变诱导，小鼠微核试验结果为阴性。结果表明，无代谢活化时染色体畸变的诱导可能是由于高盐浓度所致，表明该提取物中的致断裂剂需要代谢活化。二氯甲烷提取物在Ames试验、SCE试验和染色体畸变试验中表现出遗传毒性，而在V79细胞中未观察到基因突变诱导。结果再次表明，遗传毒性需要代谢作用。二氯甲烷提取物未诱导小鼠微核或黑腹果蝇性连锁隐性致死突变。使用各种致癌性预测模型对这些遗传毒性综合数据进行了分析。在序贯测试模型中，预测“鼻烟”的水提取物和二氯甲烷提取物因遗传毒性机制而致癌的概率均较低。使用通过组合选择进行致癌性预测（CPBS）方法，二氯甲烷提取物和水提取物被正确鉴定为非致癌物的概率分别为71%和77%。到目前为止，CPBS方法主要针对单个化合物进行了验证，因此目前在使用该方法解释结果时应谨慎。基于这些结果，应认为瑞典“鼻烟”的致癌潜力较低，这一结论与瑞典与其他国家相比口腔癌发病率较低的情况相符。
