Contraceptive steroid toxicology in the Beagle dog and its relevance to human carcinogenicity

Abstract

Problems associated with the use of the Beagle dog in chronic toxicological studies of contraceptive steroids are described. A short review is presented on the occurrence of spontaneous tumours in dogs and in bitches of various breeds. The current status of knowledge of canine reproductive hormones and endocrinology is outlined, together with effects of contraceptive steroids. The pathology and histological classification of spontaneous and induced mammary neoplasia in the dog is discussed and compared with breast cancer in women. A series of recommendations are included for future research in this field which it is hoped may resolve some of the outstanding issues and lead to a more suitable toxicological model for contraceptive steroids.

PIP: Many scientists have criticized the mandatory use of dogs for studies of the chronic toxicity of synthetic steroidal contraceptive hormones. The estimated annual incidence rates for cancer of all sites in dogs is 381.2/100,000 dogs. The estimated relative risk (R) value for the occurrence of tumors in the Beagle breed is 0.9; for malignant tumors, the R value in the Beagle is 0.8. A review of the hormonal potency of various contraceptive steroids in the Beagles indicates that progestogenic compounds generally produce a much lower progestational activity in dogs than in women, and the the predominant hormonal action of norethisterone in dogs is estrogenicity rather than progestogenicity. This weak activity for the canine species may account for some of the toxicological findings for norethisterone and related compounds in the Beagle. It is also possible that there are species differences in the relative affinities of estrogen and progesterone receptors for contraceptive steroids. Studies on long-term administration to female Beagle dogs suggest that the nodules found in the mammary gland are not histologically comparable to mammary tumors found in the human female although there is a superficial morphological resemblance to some forms of human mammary dysplasia. Several authors suggest that the results of testing progestational compounds in Beagles are unlikely to be indicative of a potential hazard to the human female. In testing megestrol acetate, it is suggested that the unique sensitivity of the canine females to megestrol acetate is exemplified by intense mammary development at dose levels 10 times the human oral contraceptive level. In contrast, daily dose levels of 500 mg/day in women as a palliative for endometrial cancer have been used with no serious side effects or mammary enlargement. Also the canine mammary gland produces certain pathological changes following administration of natural or synthetic progesterones in a way not readily seen in other species. Possible alternative models (cat, pig) for contraceptive steroid toxicological studies and recommendations for future research are discussed.