For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 273)
Diethylstilboestrol
CAS No.:
Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol
Diethylstilboestrol dipropionate
CAS No.:
Chem. Abstr. Name: (E)-4,4'-(1,2-Diethyl-1,2-ethenediyl)bisphenol dipropionate
Dienoestrol
CAS No.:
Chem. Abstr. Name: 4,4'-(1,2-Diethylidene-1,2-ethanediyl)bisphenol
Hexoestrol
CAS No.:
Chlorotrianisene
CAS No.:
Chem. Abstr. Name:1,1',l"-(1-Chloro-1-ethenyl-2-ylidene)-tris(4-methoxybenzene)
Diethylstilboestrol
A. Evidence for carcinogenicity to humans (sufficient)
Diethylstilboestrol (DES) causes clear-cell adenocarcinoma of the vagina and cervix in women exposed in utero. There is sufficient evidence that administration of oestrogens for the control of symptoms of the climacteric is causally related to an increased incidence of endometrial carcinoma; DES is no different from other oestrogens in this respect [ref: 1].
There is also clear evidence that administration of DES in large doses during pregnancy increases the subsequent risk of breast cancer and that DES increases the risk of testicular cancer in males exposed in utero.
In four follow-up studies [ref: 2-5] of exposed and nonexposed groups of women, the possible effects of DES exposure during pregnancy on subsequent breast cancer risk have been evaluated. All have shown an increased risk in exposed women; two were randomized trials [ref: 2,3]. In one [ref: 2], there were 32 (4.6%) breast cancers among 693 women exposed to an average total dose of 12 g DES, and 21 (3.1%) breast cancers among 668 control (placebo) women. In the other [ref: 3], there were four (5.0%) breast cancers among 80 women exposed to an average total dose DES of 16 g (plus ethisterone, average total dose, 14 g), compared to none of 76 controls; all 156 women were diabetic. In two studies, an exposed group and a 'matched' unexposed group were followed-up [ref: 4,5]. One [ref: 4] found 118 (4.4%) breast cancer cases in 2680 women exposed to a mean DES dose of 5 g, and 80 (3.1%) among 2566 control women. The other [ref: 5] similarly showed 38 (2.5%) breast cancer cases among 1531 women exposed to a mean DES dose of 2 g, and 24 (1.7%) cases among the 1404 control women. The overall relative risk from these four studies is 1.5 (p = 0.001).
A further group of 408 DES-exposed women (median dose, 1.5 g) was followed up and the eight breast cancer cases found were contrasted to the 8.1 cases expected on the basis of local breast cancer incidence rates [ref: 6]. If this study is considered together with the four studies described above, the overall relative risk is 1.4 (p = 0.0016).
In all five papers [ref: 2-6], the possibility is discussed that there may be a long (15-20 years) 'latent' period before the first 'DES-induced' breast cancer would be seen. Clear evidence was found in a study [ref: 4] in which there was no difference in the breast cancer rates of exposed and unexposed women until 22 years after exposure, but an increasing difference thereafter. Similarly, in another study [ref: 3], there was no case in the exposed group in the first 18 years after exposure. In a further study [ref: 5], the relative risk was 1.3 before age 50 and 1.7 thereafter, and in another [ref: 6], three cases were reported with 5.1 expected before age 50 and five cases versus 3.0 expected thereafter. In contrast, however, a randomized study [ref: 2] showed 11 exposed cases and five nonexposed cases during the first 15 years of follow-up, compared to 21 exposed cases and 16 nonexposed cases thereafter. Further data are required to settle this issue.
The four follow-up studies [ref: 2-5] of exposed and nonexposed women also included information on other possibly 'hormone-related' cancers. The occurrence of endometrial cancer was not increased in any study. The study [ref: 2] of 693 women exposed to DES and 668 controls showed increases in the occurrence of cancer of the ovary (4 exposed, 1 nonexposed), cancer of the cervix (7 exposed, 3 non-exposed) and cancer of the colon-rectum (2 exposed, 1 nonexposed); there was also a risk for cancer at these sites in the study of 1531 women exposed to DES and 1404 controls [ref: 5] (6 exposed, 2 nonexposed; 9 exposed, 6 nonexposed; 11 exposed, 7 nonexposed for the three sites, respectively). A third study [ref: 4] showed, in contrast, no elevation of rates for cancer at any other site, and there were seven deaths from cervical cancer in the control group and none in the exposed group, suggesting that matching in the control group was 'inadequate'; the authors could not identify the matching problem, and, in particular, they found that the two groups were well matched on educational level. The data are too few to draw any firm conclusions.
A greater frequency of abnormalities of the reproductive tract has been found in males exposed prenatally to DES in comparison with nonexposed controls, although the data are few. Cryptorchidism, a major risk factor for testicular cancer, is one of the associated lesions [ref: 1]. Cancer of the testis has been investigated in five case-control studies of fetal exposure to DES [ref: 7-11]. One [ref: 7] showed that 5.1% (4/78) of cases and 1% of controls had been exposed to hormones (in all likelihood DES) for bleeding; the second [ref: 8] similarly found that 5.8% (11/190) versus 2.3% (7/304) had had such exposure; the third [ref: 9] found 1.9% (2/108) versus 0 (0/108) exposed to DES; the fourth [ref: 10] found 1.0% (2/202) versus 1.0% (2/206) exposed to DES; and the fifth [ref: 11] found 1.9% (4/211) versus 0.9% (2/214) exposed to DES. The combined relative risk is 2.5 (p = 0.014).
A number of unusual tumours have been reported in women exposed to DES in utero: a fatal adenocarcinoma of the endometrium at age 26 [ref: 12]; a pituitary adenoma at age 18 [ref: 13]; an invasive squamous-cell carcinoma of the cervix at age 21 [ref: 14]; an invasive adenosquamous-cell carcinoma of the cervix at age 27 [ref: 15]; and an ovarian teratoma at age 12 [ref: 16].
There has been no further report to add to the six cases of primary breast cancer in males with prostatic cancer treated with DES [ref: 1]. A case has been reported of a Leydig-cell tumour developing in such a man treated with DES at 1 mg per day for 2.5 years [ref 17]. There has been a second case report of hepatic angiosarcoma in a man treated over a long period with DES for prostatic cancer [ref: 1,18], and a second case report of a hepatoma in a prostatic cancer patient treated with DES at 3 mg per day for 4.5 years (to diagnosis of hepatoma) [ref: 1,19]. Three renal carcinomas have been reported after exposure to DES for prostatic cancer [ref: 20,21].
B. Evidence for carcinogenicity to animals (sufficient)
DES has been tested in mice, rats, hamsters, frogs and squirrel monkeys, producing tumours principally in oestrogen-responsive tissues [ref: 1]. Female newborn mice injected with DES developed epidermoid carcinomas and granular-cell myoblastomas of the cervix and squamous carcinomas of the vagina [ref: 22]. Mice treated prenatally with DES developed adenocarcinomas of the uterus, cervix and vagina, epidermoid carcinomas of the uterine cervix and vagina and ovarian and mammary tumours [ref: 23-28]. Female mice fed diets containing DES developed cervical and endometrial adenocarcinomas, mammary adenocarcinomas, osteosarcomas and mesotheliomas [ref: 29-33]. Mice treated subcutaneously with DES had a slightly increased incidence of lymphomas and subcutaneous fibrosarcomas [ref: 34,35]. Prenatal exposure to DES potentiated mammary tumorigenesis in rats given 7,12-dimethylbenz[a]anthracene at about 50 days of age [ref: 36]. Rats given DES by subcutaneous pellet developed mammary and pituitary tumours. When these animals wee also treated with X-rays or neutrons, they developed a higher incidence of mammary tumours [ref: 37-39]. In other studies (subcutaneous, transplacental, oral), rats treated with DES developed mammary, hepatic and pituitary tumours [ref: 40-44]. When hamsters were treated prenatally with DES, females developed endometrial adenocarcinoma, squamous-cell papillomas of the cervix and vagina, and a mixed Mullerian tumour of the cervix (myosarcoma); in males, a leiomysarcoma of the seminal vesicles and a Cowper's gland adenoma were found [ref: 45]. Male hamsters castrated as adults and given DES subcutaneously developed renal tumours [ref: 46,47].
C. Other relevant data
No data were available on the genetic and related effects of DES in humans.
DES induced chromosomal aberrations in bone-marrow cells of mice treated in vivo, but data on induction of sister chromatid exchanges and micronuclei were equivocal; it induced sister chromatid exchanges in one study in rats. Unusual nucleotides were found in kidney DNA following chronic treatment of hamsters with DES. Aneuploidy was induced in human cells in vitro, but data on induction of sister chromatid exchanges. chromosomal aberrations and mutation were inconclusive; it induced DNA strand breaks, but not unscheduled DNA synthesis, except in a single study. Tests for transformation in rat and Syrian hamster embryo cells gave positive results, while results for mouse cells were negative. Aneuploidy and DNA strand breaks were induced in rodent cells in vitro, but results for chromosomal aberrations and sister chromatid exchanges were equivocal; DES did not induce mutation or unscheduled DNA synthesis, except in a single study in Syrian hamster embryo cells. It did not inhibit intercellular communication of Chinese hamster V79 cells. It induced aneuploidy in fungi, but, in most studies, it did not induce mutation, recombination or gene conversion. It did not induce mutation in a variety of bacterial and insect systems, but it was mutagenic in plants. DNA damage was not induced in fungi or bacteria. DES induced single-strand breaks in bacteriophage DNA in the presence of a horseradish peroxidase activation system [ref: 48].
References
1. IARC Monographs, 21, 131-134, 173-231, 1979
2. Bibbo, M., Haenszel, W.M., Wied, G.L., Hubby, M. & Herbst, A.L. (1978) A twenty-five-year follow-up of women exposed to diethylstilbestrol during pregnancy. New Engl. J. Med., 298, 763-767
3. Beral, V. & Colwell, L. (1980) Randomised trial of high doses of stilboestrol and ethisterone in pregnancy: Long-term follow-up of mothers. Br. med. J., 281, 1098-1101
4. Greenberg, E.R., Barnes, A.B., Resseguie, L., Barrett, J.A., Burnside, S., Lanza, L.L., Neff, R.K., Stevens, M., Young, R.H. & Colton, T. (1984) Breast cancer in mothers given diethylstilbestrol in pregnancy. New Engl. J. Med., 311, 1393-1398
5. Hadjimichael, O.C., Meigs, J.W., Falcier, F.W., Thompson, W.D. & Flannery, J.T. (1984) Cancer risk among women exposed to exogenous estrogens during pregnancy. J. natl Cancer Inst., 73, 831-834
6. Brian, D.D., Tilley, B.C., Labarthe, D.R., O'Fallon, W.M., Noller, K.L. & Kurland, L.T. (1980) Breast cancer in DES-exposed mothers. Absence of association. Mayo Clin. Proc., 55, 89-93
7. Henderson, B.E., Benton, B., Jing, J., Yu, M.C. & Pike, M.C. (1979) Risk factors for cancer of the testis in young men. Int. J. Cancer, 23, 598-602
8. Schottenfeld, D., Warshauer, M.E., Sherlock, S., Zauber, A.G., Leder, M. & Payne, R. (1980) The epidemiology of testicular cancer in young adults. Am. J. Epidemiol., 112, 232-246
9. Depue, R.H., Pike, M.C. & Henderson, B.E. (1983) Estrogen exposure during gestation and risk of testicular cancer. J. natl Cancer Inst., 71, 1151-1155
10. Brown, L.M., Pottern, L.M. & Hoover, R.N. (1986) Prenatal and perinatal risk factors for testicular cancer. Cancer Res., 46, 4812-4816
11. Moss, A.R., Osmond, D., Bacchetti, P., Torti, F.M. & Gurgin, V. (1986) Hormonal risk factors in testicular cancer. A case-control study. Am. J. Epidemiol., 124, 39-52
12. Barter, J.F., Austin, J.M., Jr & Shingleton, H.M. (1986) Endometrial adenocarcinoma after in utero diethylstilbestrol exposure. Obstet. Gynecol., 67 (Suppl.), 84S-85S
13. Cunningham, J.R., Gidwani, G.P., Gupta, M.S., Duchesneau, P.M. & Schumacher, O.P. (1982) Prolactin-secreting pituitary adenoma: occurrence following prenatal exposure to diethylstilbestrol. Cleveland Clin. Q., 49, 249-254
14. Lamb, E.J. (1977) Invasive squamous cell carcinoma of the cervix in a diethylstilbestrol-exposed offspring. Am. J. Obstet. Gynecol., 129, 924-925
15. Vandrie, D.M., Puri, S., Upton, R.T. & Demeester, L.J. (1983) Adenosquamous carcinoma of the cervix in a woman exposed to diethylstilbestrol in utero. Obstet. Gynecol., 61 (Suppl.), 84S-87S
16. Lazarus, K.H. (1984) Maternal diethylstilboestrol and ovarian malignancy in offspring. Lancet, i, 53
17. Deshmukh, A.S. & Hartung, W.H. (1983) Leydig cell tumor in patient on estrogen therapy. Urology, 21, 538-539
18. Ham, J.M., Pirola, R.C. & Crouch, R.L. (1980) Hemangioendothelial sarcoma of the liver associated with long-term estrogen therapy in a man. Dig. Dis. Sci., 25, 879-883
19. Brooks, J.J. (1982) Hepatoma associated with diethylstilbestrol therapy for prostatic carcinoma. J. Urol., 128, 1044-1045
20. Bellet, R.E. & Squitieri, A.P. (1974) Estrogen-induced hypernephroma. J. Urol., 112, 160-161
21. Nissenkorn, I., Servadio, C. & Avidor, I. (1979) Oestrogen-induced renal carcinoma. Br. J. Urol., 51, 6-9
22. Dunn, T.B. (1979) Cancer and other lesions in mice receiving estrogens. Recent Results Cancer Res., 66, 175-192
23. McLachlan, J.A. (1979) Transplacental effects of diethylstilbestrol in mice. Natl Cancer Inst. Monogr., 51, 67-72
24. McLachlan, J.A., Newbold, R.R. & Bullock, B.C. (1980) Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res., 40, 3988-3999
25. Lamb, J.C., IV, Newbold, R.R. & McLachlan, J.A. (1981) Visualization by light and scanning electron microscopy of reproductive tract lesions in female mice treated transplacentally with diethylstilbestrol. Cancer Res., 41, 4057-4062
26. Newbold, R.R. & MacLachlan, J.A. (1982) Vaginal adenosis and adenocarcinoma in mice exposed prenatally or neonatally to diethylstilbestrol. Cancer Res., 42, 2003-2011
27. Walker, B.E. (1983) Uterine tumors in old female mice exposed prenatally to diethylstilbestrol. J. natl Cancer Inst., 70, 477-484
28. Nagasawa, H., Mori, T. & Nakajima, Y. (1980) Long-term effects of progesterone or diethylstilbestrol with or without estrogen after maturity on mammary tumorigenesis in mice. Eur. J. Cancer, 16, 1583-1589
29. Highman, B., Greenman, D.L., Norvell, M.J., Farmer, J. & Shellenberger, T.E. (1980) Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethylstilbestrol or 17b-estradiol. J. environ. Pathol. Toxicol., 4, 81-95
30. Highman, B., Roth, S.I. & Greenman, D.L. (1981) Osseous changes and oesteosarcomas in mice continuously fed diets containing diethylstilbestrol or 17b-estradiol. J. natl Cancer Inst., 67, 653-662
31. Greenman, D.L., Highman, B., Kodell, R.L., Morgan, K.T. & and Norvell, M. (1984) Neoplastic and nonneoplastic responses to chronic feeding of diethylstilbestrol in C3H mice. J. Toxicol. environ. Health, 14, 551-567
32. Greenman, D.L., Kodell, R.L., Highman, B., Schieferstein, G.J. & Norvell, M. (1984) Influence of strain and age on the induction of mammary tumours by diethylstilboestrol in C3H mice. Food chem. Toxicol., 22, 871-874
33. Greenman, D.L., Highman, B., Chen, J.J., Schieferstein, G.J. & Norvell, M.J. (1986) Influence of age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine mammary tumor virus titer. J. natl Cancer Inst., 77, 891-898
34. Boján, F., Rédai, I. & Gomba, S. (1979) Induction of lymphomas by urethane in combination with diethylstilboestrol in CFLP mice. Experientia, 35, 378-379
35. Ways, S. (1982) Local induction of fibrosarcomas by diethylstilbestrol. Int. Res. Commun. System med. Sci., 10, 796-797
36. Boylan, E.S. & Calhoon, R.E. (1979) Mammary tumorigenesis in the rat following prenatal exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz(a)anthracene. J. Toxicol. environ. Health, 5, 1059-1071
37. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1979) Synergism of diethylstilbestrol and radiation in mammary carcinogenesis in female F344 rats. J. natl Cancer Inst., 63, 1071-1074
38. Holtzman, S., Stone, J.P. & Shellabarger, C.J. (1981) Synergism of estrogens and X-rays in mammary carcinogenesis in female ACI rats. J. natl Cancer Inst., 67, 455-459
39. Shellabarger, C.J., Chmelevsky, D., Kellerer, A.M., Stone, J.P. & Holtzman, S. (1982) Induction of mammary neoplasms in the ACI rat by 430-keV neutrons, X-rays, and diethylstilbestrol. J. natl Cancer Inst., 69, 1135-1146
40. Sumi, C., Yokoro, K. & Matsushima, R. (1983) Induction of hepatic tumors by diethylstilbestrol alone or in synergism with N-nitrosobutylurea in castrated male WF rats. J. natl Cancer Inst., 70, 937-942
41. Phelps, C. & Hymer, W.C. (1983) Characterization of estrogen-induced adenohypophyseal tumors in the Fischer 344 rat. Neuroendocrinology, 37, 23-31
42. Rothschild, T.C., Calhoon, R.E. & Boylan, E.S. (1985) Transplacental carcinogenicity of diethylstilbestrol (DES) in female ACI rats (Abstract No. 770). Proc. Am. Assoc. Cancer Res., 26, 195
43. Inoh, A., Kamiya, K., Fujii, Y. & Yokoro, K. (1985) Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/FU rats. Jpn. J. Cancer Res. (Gann), 76, 699-704
44. Wanless, I.R. & Medline, A. (1982) Role of estrogens as promoters of hepatic neoplasia. Lab. Invest., 46, 313-320
45. Rustia, M. (1979) Role of hormone imbalance in transplacental carcinogenesis induced in Syrian golden hamsters by sex hormones. Natl Cancer Inst. Monogr., 51, 77-87
46. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204
47. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and carcinogenic activities. Arch. Toxicol., 55, 110-118
48. IARC Monographs, Suppl. 6, 250-256, 1987
Dienoestrol
A. Evidence for carcinogenicity to animals (limited)
Dienoestrol was tested in female guinea-pigs by subcutaneous injection and in female mice by intravaginal administration. Although these experiments indicated induction of 'uterine tumours' in guinea-pigs and of ovarian tumours in mice, they were regarded as inadequate [ref: 1]. Renal tumours were produced by administration of a-dienoestrol in male hamsters castrated as adults [ref: 2,3]. In noninbred rats, dienoestrol given prenatally and neonatally did not increase tumour incidence [ref: 4].
B. Other relevant data
No data were available on the genetic and related effects of dienoestrol in humans.
There are two stable stereoisomers of dienoestrol - Z,Z-dienoestrol (cis,cis-dienoestrol, b-dienoestrol) and E,E-dienoestrol (trans,trans-dienoestrol, a-dienoestrol). E,E-Dienoestrol is the principal constituent of dienoestrol-containing medications, whereas Z,Z-dienoestrol is a metabolite of diethylstilboestrol. Z,Z-Dienoestrol induced sister chromatid exchanges in human fibroblasts in vitro. Z,Z-Dienoestrol, but not E,E-dienoestrol, transformed cultured hamster cells. Z,Z-Dienoestrol produced single-strand breaks in hamster cells in the absence of an exogenous metabolic system, whereas both Z,Z- and E,E-dienoestrol gave weakly positive results in tests for unscheduled DNA synthesis in hamster cells only in the presence of a metabolic system. Z,Z-Dienoestrol did not induce single-strand breaks in bacteriophage DNA in the presence of a horseradish peroxidase activation system. Z,Z-Dienoestrol and E,E-dienoestrol were not mutagenic to bacteria [ref: 5].
References
1. IARC Monographs, 21, 161-171, 1979
2. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204
3. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and carcinogenic activities. Arch. Toxicol., 55, 110-118
4. Ird (Y.A. (1983) Blastomogenesis induced in rats by transplacental treatment with strogens (Russ.). Vopr. Onkol., 29, 61-66
5. IARC Monographs, Suppl. 6, 336-337, 1987
Hexoestrol
A. Evidence for carcinogenicity to animals (sufficient)
Hexoestrol was tested for carcinogenicity in intact male hamsters and in males castrated as adults by subcutaneous implantation as a pellet, producing renal tumours, some of which were described as renal carcinomas, in 85-100% of tested animals [ref: 1-3].
B. Other relevant data
No data were available on the genetic and related effects of hexoestrol in humans. Unusual nucleotides were found in kidney DNA of hamsters treated with hexoestrol in vivo. The compound was not mutagenic to bacteria [ref: 4].
References
1. Li, J.J., Li, S.A., Klicka, J.K., Parsons, J.A. & Lam, L.K.T. (1983) Relative carcinogenic activity of various synthetic and natural estrogens in the Syrian hamster kidney. Cancer Res., 43, 5200-5204
2. Li, J.J. & Li, S.A. (1984) Estrogen-induced tumorigenesis in hamsters: roles for hormonal and carcinogenic activities. Arch. Toxicol., 55, 110-118
3. Liehr, J.G., Ballatore, A.M., Dague, B.B. & Ulubelen, A.A. (1985) Carcinogenicity and metabolic activation of hexestrol. Chem.-biol. Interactions, 55, 157-176
4. IARC Monographs, Suppl. 6, 336-337, 1987
Chlorotrianisene
A. Evidence for carcinogenicity to animals (inadequate)
Chlorotrianisene was tested in only one experiment in rats by oral administration. The data were insufficient to evaluate the carcinogenicity of this compound [ref: 1].
B. Other relevant data
No data were available to the Working Group.
Reference
1. IARC Monographs, 21, 139-146, 1979
Overall evaluation
Nonsteroidal oestrogens are carcinogenic to humans (Group 1).
N.B. - This evaluation applies to the group of chemicals as a whole and not necessarily to all individual chemicals within the group.
For definition of the italicized terms, see Preamble Evaluation.
Also previous evaluations: Vol. 6 (1974); Vol. 21 (1979)
See Also:
Toxicological Abbreviations