Possible Cancer Hazard Presented by Feeding Diethylstilbestrol to Cattle

Introduction of the powerful drug diethylstilbestrol into the nation’s food supply prompts consideration of the actions of this compound. It is known to induce cancer.^1,2 It has also been found to stimulate weight gain. For the latter reason, there has developed a practice of administering this drug to poultry and beef cattle in the United States.³

It has been estimated that more than 30 million chickens per year are implanted with pellets of diethylstilbestrol and that approximately half of the feed-lot cattle in the country are now given feeds to which this drug has been added. In poultry, the pellets are intended to be inserted at the base of the skull on the supposition that this part will be discarded and not eaten. But among nine lots of poultry coming into the New York market and examined by inspectors of the Food and Drug Administration, about 35 per cent of the birds were stated to contain such pellets in the neck. Similar findings emerged from subsequent investigations, and the residual diethylstilbestrol was reported as 3 to 24 mg. per bird.⁴ It has been claimed that no appreciable quantities of diethylstilbestrol can be demonstrated in the tissues of cattle fed this drug,³ but this claim may convey a false sense of security for reasons subsequently given in this presentation.

Diethylstilbestrol can be made under conditions involving exposure to a temperature of 428 F. for several hours.⁵ The temperature recommended for roasting chickens is 350 F. Temperatures of only 140 to 180 F are found in the interior of roasts of beef.⁶ From these figures, it is apparent that diethylstilbestrol would not be destroyed by cooking and could be conveyed to consumers of meat containing it.

It thus seems pertinent to review the effects that this compound can exert. Administration of estrogens, among which diethylstilbestrol is one of the most potent, has led to a wide range of pathologic changes in human beings and in animals. In mice, rats, or guinea pigs, estrogens can induce polyps, fibroids, and cancers of the uterus, cancers of the cervix, cancers of the breast, hyperplasia of prostatic stroma and of endometrium, tumors of the testicle and hypophysis, and leukemias.

In the experience of one of us (R. I.), uterine tumors have frequently been found in guinea pigs given as little as 1.5 mg. of diethylstilbestrol or other estrogens in subcutaneously implanted pellets.^7,8 Indeed, tumors have resulted in guinea pigs exposed to as little as 8 g. (0.008 mg.) of diethylstilbestrol per day.⁷ Lower dosage levels have not yet been tested in guinea pigs, but in current experiments a pellet removed from a guinea pig one year after implantation has been found to retain sufficient activity to induce a tumor upon reimplantation into another animal.

Investigators at the National Cancer Institute⁹ have reported that cancers of the breast can be induced in mice by as little as 0.07 ????g. of diethylstilbestrol per day. This dosage sufficed to induce breast cancer in about 50 per cent of male mice, who do not develop such tumors in absence of exposure to an estrogen. A total dose of 30 ????g. was effective in these experiments in which the drug was administered in a subcutaneously implanted pellet. These and other investigators found that diethylstilbestrol also induced tumors readily when given to mice by mouth. Normal mice excrete between 0.05 and 0.1 ????g. of estrogen per day.¹⁰ So delicate is the physiologic balance that exposure to an approximately equal additional amount (0.07 ????g.) of estrogen (diethylstilbestrol) per day suffices to induce cancer, as previously mentioned.

From these findings, it is obvious that the cancer-producing dose of this drug approaches the infinitesimal. Claims that no appreciable quantities of it can be demonstrated in tissues of cattle to which it has been fed must therefore be carefully scrutinized as to the sensitivity and accuracy of the test methods. An equally cogent consideration is that the fundamental mechanism of cancer induction by diethylstilbestrol is not understood. Many tumors are known to be caused by viruses.² In mice, cancer of the breast has been traced to a virus, but, for its cancer-producing activity, this virus is dependent upon stimulation by estrogens, such as diethylstilbestrol. This virus remains in the tissues and exerts its neoplastic effects long after cessation of administration of estrogens. Absence of detectable estrogen in the tissues of animals treated with or fed such a substance thus offers no assurance of the absence of a cancer hazard in such tissues.

A great body of evidence shows that cancer-inciting chemicals can exert their effects in catalytic quantities, inducing changes in cells which are mediated by unknown substances transmitted from cell to cell long after the original cancer-inciting material ceases to be demonstrable in the tissues.² No assurance of the absence of such substances can be offered consumers of tissues from animals treated with or fed a carcinogen, such as diethylstilbestrol.

In human beings a variety of pathologic changes have been found to follow administration of estrogens. In women well past the menopause, the course of breast cancer is slowed by estrogens, but in somewhat younger women it is accelerated.¹⁰ There are claims for primary initiation of cancer in women by estrogens,¹² but these have been few in contrast to the great number and diversity of tumors following estrogenic treatment of animals. Now it has been found from animal experiments that the spacing of doses greatly influences the yield of tumors. Most important, it has been learned from animal work that intermittent administration of very large doses of estrogens is far less effective in inducing tumors than is a continuing exposure to an extremely minute dose. This phenomenon has been repeatedly observed by one of us (R.I.) in experiments conducted over a period of nearly 20 years with Lipschutz.⁷ It is a continuing exposure to extremely minute doses that is to be feared from the introduction of estrogens into the food supply.

A prime consideration is the long period of time that elapses between first exposure to a carcinogen, such as diethylstilbestrol, and eventual appearance of a tumor. In animal experiments, exposure is customarily begun early in life and the majority of tumors arise when the animals are old. Experience in the results of administration of estrogens to human beings has been largely limited to treatment of conditions arising fairly late in life. By comparison, the majority of human beings thus far exposed would complete their life span before passage of sufficient time to observe a carcinogenic effect of estrogens. The introduction of estrogens into the food supply, however, presents the problem of exposure of human beings from birth onward. That human beings are not immune to the cancer-inciting action of estrogens is shown by the fact that there are on record some 17 cases of cancer of the breast in men given estrogens, including diethylstilbestrol.^13-15

Figures were presented to this symposium¹⁴ which, according to our understanding, represent the finding of about 1 ????g. of diethylstilbestrol per pound in the tissue of a steer given the prescribed amount of 10 mg. of this drug in feed. One pound of such tissue would thus contain about 14 times the amount of diethylstilbestrol needed as a daily dose to produce cancer in mice, for, as previously stated, 0.07 ????g. of diethylstilbestrol per day sufficed to elicit cancer in about 50 per cent of mice. Furthermore, claims for the absence of diethylstilbestrol in tissues have been based on a method whose limit of sensitivity³ is, according to our calculations, in the range of 1 ????g. per 1.1 lb. This means that a pound of meat, certified as free of diethylstilbestrol, could contain nearly 14 times the amount of this drug necessary to induce cancer by a daily dose to mice. In the case of market poultry found to contain up to 24 mg. of diethylstilbestrol per bird,⁴ one is dealing with an amount roughly equivalent to 342,000 times the daily dose necessary to produce cancer in mice.

It would therefore seem prudent that further careful consideration be given the matter of adding to the cycle of food supply a drug known to initiate or aggravate a serious disease.

 

References Cited:

1. Hartwell, J. L.: “Survey of compounds which have been tested for carcinogenic activity,” Washington, D. C., U. S. Pub. Health Service Publication No. 149, 1951.
2. Homburger, F., and Fishman, W. H.: The Physiopathology of Cancer, New York, Paul B. Hoeber, 1953.
3. Fournier, W. C.: “New hormone drug fattens cattle quicker,” The Wall Street Journal, Sept, 9, 1955.
4. Wickenden, L.: Our Daily Poison, New York, Devin-Adair, 1955.
5. Twombly,G. H.: “Tissue localization and excretion routes of radioactive diethylstilbestrol,” Acta Union Internat. contre Cancer, 8:882-888, 1952.
6. Farmer, F.: The Boston Cooking School Cook Book, Boston, Little, Brown & Co., 1944.
7. Lipschutz, A.: Steroid Hormones and Tumors, Baltimore, Williams & Wilkins Co., 1950.
8. Lipschutz, A.; Iglesias, R., and Vargas, L.: “Uterine and extra-uterine localizations of experimental fibroids induced in guinea pigs by prolonged administration of estrogens,” Proc. Soc. Exper. Biol. & Med. 45:788-792, 1940.
9. Staff Of The National Cancer Institute. U.S.P.H.S. “A symposium on mammary tumors in mice.” Washington, D. C.. Am. A. Advancement of Science, Publication No. 22, 1945, p. 97.
10. Aub, J. C.; Karnofsky D., and Towne, L. E.: “Sex hormone excretion rates in high and low tumor strains of mice,” Cancer Research 1:737, 1941.
11. Escher, G. C.: “Hormone therapy in advanced mammary carcinoma,” M. Clinics North America, 36:681-688. 1952.
12. Novak, E.: “Uterine adenocarcinoma in a patient receiving estrogens,” Am. J Obst & Gynec. 62:688-690, 1951.
13. Hueper, W. C.: “Recent developments in environmental cancer,” A. M. A. Arch. Path. 58:475–523, 1954.
14. Graves, G. and Harris, H.: “Carcinoma of the male breast with axillary metastasis following stilbestrol therapy,” Ann. Surg. 135:411-414, 1952.
15. Jakobsen, A.: “Bilateral mammary carcinoma in the male following stilbestrol therapy,” Acta Path. et Microbiol Scandinav. 31 61-65, 1952.
16. Gossett, F. O.: “The feeding of high levels of diethylstilbestrol to beef animals.” In: Symposium on Medicated Feeds, New York, Medical Encyclopedia, Inc., 1956.