Diethylstilbestrol carcinogenicity

Diethylstilbestrol, mentioned in Chapters 5 and 9 as a synthetic estrogen that is also a human carcinogen, was used in the United States from the 1950s until 1979 as a growth promoter in sheep and cattle. Small amounts of this drug, added to animal feed or implanted in the flesh of animals ears, increase feed efficiency, and it was very widely used for this purpose. 

Growth Promotants. Diethylstilbestrol was the major growth promo-tant in use for many years. It was very effective, increasing weight gain in steers by 15 to 19% and feed efficiency by up to 12%. However, it has now been banned in most countries because of its reported carcinogenicity. 

Diethylstilbestrol, hexestrol, and dienestrol are all stilbene estrogens currently banned worldwide for use in food-producing animals. They are genotoxic, not easily metabolized compounds, which are considered capable of irreversibly initiating the carcinogenic process even at small residue concentrations. 

In cattle feces, 64% of the total residues was identified as diethylstilbestrol, 23% as 3-(p-hydroxyphenyl)-2-hexene-4-one, and less than 1% as 4 -hydroxypro-piophenone (43). The identification of 4 -hydroxypropiophenone as a metabolite of diethylstilbestrol implies that dienestrol is formed through an epoxide-diol pathway and that these metabolites show electrophilic reactivity (45). These observations have to be seen in connection with the mutagenic and carcinogenic activity of diethylstilbestrol and possibly also the other stilbene estrogens. 

Williams GM, Iatropoulos M, Cheung R, Radi L, Wang CX. Diethylstilbestrol liver carcinogenicity and modification of DNA in rats. Cancer Lett 1993 68(2-3) 193-8. 

The three principal classes of cytotoxic agents used in the treatment of cancer all contain carcinogens, for example, Melphalen, a nitrogen mustard, adriamycin, an antitumor antibiotic, and methotrexate, an antimetabolite. Diethylstilbestrol (DES), a drug formerly widely used, has been associated with cancer of the cervix and vagina in the offspring of treated women. 

The results of the studies conducted on the 14 chemicals selected by the ILSI project were summarised by Eastin et al. (2001). Most studies confirmed the hypothesis that the dermal Tg.AC model responds to both mutagenic and nonmutagenic carcinogens. However, data from these studies suggested that the mechanism of action could be fundamental in obtaining the expected positive response. For example, topical application of ethinyl oestradiol, clofibrate and diethylstilbestrol gave clear positive results, whereas cyclosporin A was positive only in females and melphalan, phenacetin and cyclophosphamide did not produce any papillomas at SOA. The lack of receptor sites in the skin for these last compounds or selectivity between tissues for proliferative activity of some chemicals, could explain the negative responses. 

Fischer 344 rats were given 3,2 -dimethyl-4-aminobiphenyl (a prostate carcinogen) at 50 mg kg body weight 10 times at 2-week intervals, and then, from week 20, testosterone propionate and/or diethylstilbestrol by subcutaneous silastic implant for 40 weeks, as seven cycles of 30-day treatment and 10-day withdrawal. Intermittent administration of testosterone resulted in suppression of the development of ventral prostate adenocarcinomas and slight (nonsignificant) increases in the incidences of invasive carcinomas of the lateral prostate and seminal vesicles. Diethylstilbestrol completely suppressed tumorigenesis, and the combination with testosterone propionate inhibited prostate tumor development. 

According to the US Environmental Protection Agency s Office of Flealth and Environmental Assessment diethylstilbestrol is considered to be a group A human carcinogen, which is based on sufficient evidence in humans and sufficient evidence in animals. 

DES (diethylstilbestrol), xiii, 106, 115, 206 detoxification, 34 developmental toxicity, 103 dibenz(a,h)anthracene, 112 diet, 5, 13-14,106 as exposure pathway, 13-14 chemical composition of, 5 effect on absorption of chemicals, 29 natural carcinogens in, 229-31 role in cancer, 116—20, 154-6 role in cancer prevention, 230 Dioscorides, 39 dioxin, xiii, 54, 164, 180 distribution of chemicals in body, 31-2 DNA damage, 150-3, 156 Doll, R. (Sir), 117-20, 155, 177 Donora, Pennsylvania, 81 dose, 16,39,48,71 absorbed, 27-31, 161 acute, 160... 

Certain important carcinogens such as benzene, diethylstilbestrol (and ETU) are reported to be non-mutagenic in standard mutation assays, but are found to be involved in mitotic spindle disruption and induction of aneuploidy [57]. ETU was ineffective in increasing the frequency of mitotic crossing-over of forward mutation (Table 10.4). 

Diethylstilbestrol, a synthetic estrogen previously used to promote growth of beef cattle, until it was found to be potentially carcinogenic at the levels found in meat from treated cattle. 

In contrast to the above results, DDE has been detected as a mutagen in cultured Chinese hamster ovary cells. The carcinogenic estrogen, diethylstilbestrol (DES), also is missed by all of the mutagenesis-based assays which may reflect the operation of another mechanism of cancer induction in the case of hormone induced cancers. It should be noted, however, that a... 

Comparative Dose Response Data There are only a limited number of cases in which it has been possible, even on a crude level, to compare animal and human dose responses to the same carcinogens. The paucity of data in this area is related to the fact that in most epidemiological studies the actual doses of the toxic substance is not known with certainty and that while complete dose response curves can be obtained in animal studies, such studies are very expensive. A systematic attempt to estimate human exposures and compare human and animal dose response relationships for several known carcinogens has been made and is contained in a report by the National Academy of Sciences and National Research Council on Environmental Studies Board on Pest Control.The carcinogens for which responses were compared in the study were benzidine chlornaphazine diethylstilbestrol aflatoxin Bl vinyl chloride, and cigarette smoke. 

The synthetic estrogen diethylstilbestrol undergoes a similar attack. Despite its relatively hindered character, the central double bond is converted to the corresponding epoxide which was once believed to be the ultimate carcinogenic metabolite (Fig. 31.11). 

The early work on requirements for confirmatory mass spectrometric methods was undertaken to address a regulatory requirement for the analysis of carcinogens established in 1977 by the US Food and Drug Administration. A paper published in 1978 demonstrated the minimum number of peaks and the specifications for relative ion abundances for each peak required to uniquely identify diethylstilbestrol from a GC-MS spectral library containing El spectra of... 

Estrogens Diethylstilbestrol En , G Possible carcinogenic effect on fetus if taken during earfy pregnancy. 

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