rat experiments used the same three dose groups, but the strain of rat and the number of rats per dose group varied from experiment to experiment.

The CSM report itself presented no tests of statistical significance in the comparisons of tumors in the treated and control animals. The analysis presented in the CSM report also did not take into account mortality during the course of the experiment, nor was any attempt made to determine whether there were dose-response relationships. These problems hamper interpretations of the results of the study, but the information is useful depite its limitations.

Mice who were treated with estrogen alone showed no excess of malignant mammary tumors. Mice treated with any of the six progestogens alone or with any of the combinations of estrogen and progestogen also showed no excess of malignant mammary tumors. In some experiements, female rats treated with ethinyl estradiol or mestranol alone had an increase in malignant mammary tumors (Table D-1). An excess of malignant mammary tumors also appeared in male rats treated with norethynodrel alone (Table D-2). In both male and female rats, an increase in malignant mammary tumors occurred following treatment with a norethynodrel/mestranol combination and norethindrone/mestranol combination, but not following treatment with other combinations (Table D-3). Female rats showed an excess of malignant mammary tumors following treatment with a combination of ethynodiol diacetate and mestranol.

Review of these experiments leads to several conclusions. First, estrogens alone, some progestogens, and some estrogen/progestogen combinations cause an increase in the occurrence of malignant mammary tumors in at least some strains of rats and mice. Second, there is strong evidence that progestogens modify the effect of estrogen on the occurrence of malignant mammary tumors in rats, as is also shown in experiments by other investigators (Schardein, 1980). Last, the effects of estrogens and progestogens on mammary cancer in mice and rats are strain specific (see also Rudali et al., 1971).

Beagle Dogs

The FDA began to require long-term studies of contraceptive steroids in beagles as a precondition for approval for marketing following the observation that one progestogen (MK-665, or ethynerone) caused high rates of mammary tumors in beagles even at doses that were a low multiple of the human contraceptive dose. Benign mammary tumors are considered an established precursor of malignant mammary tumors in beagles, and the beagle mammary response to



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