Synergism in carcinogenesis

Six examples of exposure of humans to two carcinogens were found that satisfied the minimum requirements for analysis of whether the carcinogens acted in synergism. In all instances, the risk ratio for cancer in the group exposed to both carcinogens was equal to or greater than the product of the risk ratios of the singly exposed groups. These findings underline the danger of double exposure, even though they imply that some and not all pairs of carcinogens act in this way. Because the six studies did not extend to the end of the life-spans of the exposed individuals, the data may be skewed by the life-shortening effect of promoters. Nevertheless, the findings have implications regarding the employment of people who already having been exposed to one recognized carcinogen are in a job where they may receive additional exposure from a second carcinogen known to multiply their risk of cancer. Analyses of animal tests on synergism indicated that most published studies lack dose-response data for each of the two carcinogens, which are vital for definitive proof of synergism. Suggestions for performance of such tests are given. The theoretical basis underlying the concept of synergism is examined, equations for its evaluation are given, and examples of statistical tests for its presence are presented. The conclusion regarding the mechanism of action was that synergism occurs if the rate-limiting step in the generation of a single type of tumor differs for each of two interacting carcinogens.