The skin tumorigenic and carcinogenic effects of different doses, numbers of dose fractions amd concentrations of 7,12-dimethylbenz[a]anthracene in acetone applied on hairless mouse epidermis. Possible implications for human carcinogenesis

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Abstract
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 ∽50 and ∽26 µg 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 µg DMBA gave a tumor rate of ∽40%, whereas the same dose divided into 50 doses of 1µg gave a tumor rate of almost 100%. The final tumor yield increased from ∽45 tumors per 32 animals after a single dose of 51.2 µg DMBA to ∽250 tumors per 32 animals after 50 applications of 1 µg DMBA. The final number of carcinomas per 32 animals was one carcinoma after a single application of 51.2 µg DMBA, and 40 carcinomas after 50 applications of 1 µg 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.

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