International Agency for Research on Cancer (IARC) - Summaries & Evaluations


VOL.: 21 (1979) (p. 173)

5. Summary of Data Reported and Evaluation

(N.B. - This section should be read in conjunction with the General Remarks on Sex Hormones and with the General Conclusions on Sex Hormones.)

5.1 Experimental data

Diethylstilboestrol was tested in mice and rats by oral administration; in mice by local application; in mice, rats, hamsters and monkeys by subcutaneous implantation; and in mice, hamsters and dogs by subcutaneous injection. It was also tested by prenatal exposure in mice and hamsters and by neonatal exposure in mice and rats. Its administration to mice resulted in an increased incidence of mammary and lymphoid tumours in both males and females, and of interstitial-cell tumours of the testis in males and ovarian tumours in females; cervical and vaginal tumours were observed in females, including those exposed prenatally and on the first day of life. In rats, increased incidences of pituitary, mammary and bladder tumours (in conjunction with calculi) were observed. In hamsters, a high incidence of renal tumours was observed in castrated males and females and in intact males, but not in intact females. Following prenatal exposure of hamsters, tumours of the uterus, cervix and vagina were observed in female offspring, and tumours of the accessory sex organs occurred in males. In squirrel monkeys, malignant mesotheliomas of the uterine serosa were observed.

In another study, rats were given s.c. injections of 0.015-0.6 mg/kg bw DES on days 13, 16, 18 and 20 of pregnancy and/or 0.2-10 mg/kg bw DES for 3 weeks post partum. Genital tumours (2 vaginal squamous-cell carcinomas, 1 endometrial adenocarcinoma, 1 ovarian adenocarcinoma) were observed among 10 female offspring. None of the controls developed such tumours (Vorherr et al., 1979).

Another study has been reported in which male Syrian golden and European hamsters were implanted subcutaneously with a 25-mg DES pellet. The animals developed adenomas and adenocarcinomas of the kidney and adenohypophysis and adenomas of the testes and adrenal glands. European hamsters, which are more sensitive, also developed liver tumours (adenomas, cholangiocellular carcinomas and hepatocellular carcinomas) (Reznik-Schüller, 1979).

In most studies by pellet implantation, an accurate assessment of the effective carcinogenic dose could not be made. After oral administration, the lowest statistically significant dose that produced mammary carcinomas in mice was about 6 mg/kg bw per day. This dose is similar to that of diethylstilboestrol used in humans in the control of symptoms of the climacteric (10 mg/kg bw per day) and 30 times less than the dose given for the control of mammary or prostatic cancer (300 mg/kg bw per day).

Diethylstilboestrol dipropionate was tested by subcutaneous injection in rats and frogs, producing pituitary tumours in rats and tumours of the haematopoietic tissue in frogs.

Subcutaneous injection of polydiethylstilboestrol phosphate in hamsters produced renal tumours.

Diethylstilboestrol is embryolethal for pre- and postimplantation embryos in some species and causes teratogenic effects on the genital tract, which may be of significance for the carcinogenicity observed in these tissues.

5.2 Human data

Diethylstilboestrol taken during pregnancy has been shown to be causally associated with an increase in vaginal and cervical clear-cell adenocarcinoma in daughters, primarily in those between the ages of 10 and 30 years. The risk appears to be in the order of 0.14-1.4/1000 exposed daughters up to the age of 24 years. Because of the young age of the population at risk, further estimates of cancer risk cannot be made at this time.

Non-neoplastic epithelial and structural changes of the female genital tract have frequently been observed in the daughters of women exposed to diethylstilboestrol during pregnancy; these changes include transverse fibrous cervical and vaginal septa, vaginal adenosis and cervical ectropion. Non-malignant structural changes have been reported in the reproductive tracts of male children of exposed women; but the effect of diethylstilboestrol on fertility, if any, is uncertain. Cryptorchidism and hypoplastic testes observed in one study have been shown to be related to exposure to diethylstilboestrol; these conditions can predispose to malignant changes, but an increased risk of malignancy in males has not been demonstrated.

There appears to be an increased risk of endometrial carcinoma in young women with Turner's syndrome who were treated with diethylstilboestrol.

A few cases have been reported of breast cancer in men treated with diethylstilboestrol for metastatic prostatic carcinoma. Although a modest excess of breast cancer was observed in one study of mothers exposed to diethylstilboestrol, the difference from that in controls was not statistically significant.

Evidence strongly suggests that the administration of oestrogens for the control of symptoms of the climacteric is causally related to an increased incidence of endometrial carcinoma; diethylstilboestrol is no different from other oestrogens in this respect.

5.3 Evaluation

Diethylstilboestrol is causally associated with the occurrence of cancer in humans. There is also sufficient evidence for its carcinogenicity in experimental animals.

For definition of the italicized terms, see Preamble Evaluation.

Previous evaluation: Vol. 6 (1974)

Subsequent evaluation: Suppl. 7 (1987)

Last updated: 6 April 1998

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       Toxicological Abbreviations