Iversen O H
Institute of Pathology, University of Oslo, Norway.
Carcinogenesis. 1991 Mar;12(3):493-502. doi: 10.1093/carcin/12.3.493.
Groups of hairless mice were painted with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) dissolved in reagent-grade acetone in various doses, dose fractions and concentrations. The animals were examined once a week for an appropriate time period and skin tumors were registered and classified as tumors (all tumors appearing) and as malignant tumors. The results show that dividing a particular dose of DMBA into an increasing number of applications was the factor that had the greatest tumorigenic and carcinogenic effect. This was found for total doses of 100, approximately 50 and approximately 26 micrograms DMBA. Similarly, increasing the size of the dose increased the effect on the tumor and carcinoma crop, but to a less pronounced event than splitting the dose into several fractions. The most striking of these effects was that a single dose of 51.2 micrograms DMBA gave a tumor rate of approximately 40%, whereas the same dose divided into 50 doses of 1 microgram gave a tumor rate of almost 100%. The final tumor yield increased from approximately 45 tumours per 32 animals after a single dose of 51.2 micrograms DMBA to approximately 250 tumors per 32 animals after 50 applications of 1 microgram DMBA. The final number of carcinomas per 32 animals was one carcinoma after a single application of 51.2 micrograms DMBA, and 40 carcinomas after 50 applications of 1 microgram DMBA. The paper includes a discussion on how these findings may be explained in terms of the complicated series of events that constitutes carcinogenesis. If it is biologically plausible to regard agents for which there is sufficient evidence for carcinogenicity in experimental animals as representing a carcinogenic risk to humans, then it may also be plausible and prudent to infer that the dose schedule that represents the highest tumorigenic hazard for mouse skin may generally also be the dose schedule that involves the highest risk for humans. Thus, repeated exposure to small doses may be the most hazardous situation. This is unfortunately the way many human beings are exposed to cigarette smoke, sunshine and carcinogens in food, water, air and at the work place. As shown in a previous paper, an increasing time interval between each dose may also increase the risk.
将无毛小鼠分组，用溶解于试剂级丙酮中的致癌物质7,12 - 二甲基苯并[a]蒽（DMBA）以不同剂量、剂量分数和浓度进行涂抹。在适当的时间段内每周对动物检查一次，记录皮肤肿瘤并将其分类为肿瘤（所有出现的肿瘤）和恶性肿瘤。结果表明，将特定剂量的DMBA分成越来越多的涂抹次数是具有最大致瘤和致癌作用的因素。在DMBA总剂量为100微克、约50微克和约26微克时均发现了这一点。同样，增加剂量大小会增加对肿瘤和癌瘤数量的影响，但不如将剂量分成几个部分的影响明显。这些影响中最显著的是，单次剂量51.2微克的DMBA产生的肿瘤发生率约为40%，而相同剂量分成50次每次1微克的涂抹则产生的肿瘤发生率几乎为100%。最终肿瘤产量从单次剂量51.2微克的DMBA后每32只动物约45个肿瘤增加到50次每次1微克涂抹后每32只动物约250个肿瘤。每32只动物的癌瘤最终数量在单次涂抹51.2微克的DMBA后为1个癌瘤，在50次每次1微克涂抹后为40个癌瘤。本文讨论了如何根据构成致癌过程的一系列复杂事件来解释这些发现。如果有充分证据表明在实验动物中具有致癌性的物质对人类也构成致癌风险在生物学上是合理的，那么推断对小鼠皮肤具有最高致瘤危害的剂量方案通常也可能是对人类涉及最高风险的剂量方案也可能是合理和谨慎的。因此，反复接触小剂量可能是最危险的情况。不幸的是，许多人接触香烟烟雾、阳光以及食物、水、空气和工作场所中的致癌物就是这种方式。如前一篇论文所示，每次剂量之间增加时间间隔也可能增加风险。
