The drug has caused a number of maladies to daughters who were exposed in utero to the drug, the most serious of which is clear cell adenocarcinoma, a rare form of vaginal cancer.
The Food and Drug Administration (FDA) withdrew its approval of DES as a miscarriage preventative in 1971, and since then the focus has shifted to products liability actions filed against the drug manufacturers. The plaintiffs have been largely unsuccessful in these actions, although some innovative judicial theories have recently been advanced in allowing recovery.
This article will examine the history of this drug, how it was used and regulated as well as the subsequent legal turmoil and the proffered resolutions to the quandary. The impact of these theories and of proposals to “further strengthen product liability laws as a substitute for direct government intervention“‘ will also be studied.
From the Diethylstilbestrol Registry, an analysis of 57 cases of genital clear cell adenocarcinoma is presented from the state of California, the most populous state in the United States. Approximately two-thirds of these patients have positive histories of prenatal diethylstilbestrol exposure.
The majority of patients had early-stage genital cancer. Generally, early-stage clear cell cancer is successfully treated with radical pelvic surgery. A carefully structured screening program of the DES exposed patient is advised.
Sources and more information
International surgery, Johnston GA Jr, Jones HA., 1983 Jul-Sep;68(3):257-61, NCBI PMID: 6662641.
Patients exposed prenatally to diethylstilbestrol (DES) have been shown to have a number of significant health risks that may be considered in the evaluation of this population. Neoplastic lesions of the cervix and vagina have been observed in a few patients. Increased prevalence of squamous intraepithelial neoplasms has been reported by several large clinical centers, and a recent observation of ovarian neoplasms has been reported. The significance of these observations remains to be substantiated. Anatomic deformities of the cervix, vagina, uterus, and fallopian tubes have been associated with increased pregnancy loss or infertility. The epithelial abnormalities of adenosis and cervical erosion essentially hallmark prenatal exposure to diethylstilbestrol. These changes are in themselves not malignant or premalignant and rarely warrant therapy.
Sources and more information
Health risks and effects of prenatal exposure to diethylstilbestrol, The Journal of family practice, NCBI PMID: 6848637, 1983 Jan;16(1):51-4.
In 1983, researchers “ identified the way DES causes cancer as being through it inducing aneuploidy, or abnormal numbers of chromosomes in cells. It interferes with the process of allocating chromosomes during cell division, so that some cells end up with too many or too few chromosomes. These cells can later become cancerous.
This is something that appears to be related to it’s chemical structure rather than it acting as an estrogen, since tamoxifen, a drug which is an antiestrogen, but whose chemical structure shares some similarities with DES, causes similar changes to cells and is also a carcinogen.
This book appears to confirm that DES induces cancer through inducing aneuploidy, not by acting as a hormone. ”
1983 Study Abstract
Diethylstilbestrol (DES) has been demonstrated previously to induce morphological and neoplastic transformation of Syrian hamster embryo cells in the absence of any measurable induction of gene mutation. To determine if DES induces cell transformation by a genetic mechanism at the chromosomal level, the effect of DES on structural aberrations and numerical chromosome changes was examined in asynchronous and synchronized cells. Over the concentration range which is optimal for cell transformation, DES failed to induce any increase in chromosome aberrations in the cells. In contrast, significant numerical chromosome changes were observed in DES-treated cultures. The percentage of metaphases with a near diploid chromosome number increased to 19% at 48 hr after treatment. By comparison, cells from control cultures contained only 1 to 2% aneuploid metaphases with a near diploid chromosome number. No significant increase in the number of metaphases with a near tetraploid number (>70) of chromosomes was observed in the DES-treated cultures. DES induced both chromosome loss and gain, and no significant difference was detected between the number of hyperdiploid and hypodiploid cells. Chromosome loss or gain was observed for chromosomes in each karyotype group. These findings suggest that DES induces chromosome nondisjunction. Synchronized cell cultures were obtained by first growing the cells in 1% serum and then in 10% serum with hydroxyurea which blocked the cells at the G1-S border. Upon release of the hydroxyurea block, the cells entered into S phase in a very synchronous manner. The cells were treated for 3 hr during one of four time periods after hydroxyurea release. During the first period, the cells were primarily in early S phase, while the second period included cells in late S phase. During the third period most of the cells were undergoing mitosis, while in the fourth period most of the cells were in G1 phase, although some mitotic cells were observed. Treatment of the synchronized cells with DES during early or late S phase resulted in little morphological transformation. However, treatment during the third period, when the majority of the cells were in mitosis, resulted in a peak of transformation which was 15 times the level observed in cultures treated in early or late S phase. Treatment during the fourth time period resulted in a reduced level of cell transformation. Treatment of synchronized cultures with DES resulted also in a cell cycle-dependent induction of aneuploid cells which paralleled the induction of cell transformation, with the greatest level observed following treatment during mitosis. No increase in the percentage of polyploid metaphases or chromosome aberrations was observed in the DES-treated synchronized cells. Parallel dose-response curves for cell transformation and aneuploidy induction by DES were observed when the synchronized cultures were treated during the mitotic phase of the cell cycle. Possible mechanisms for DES-induced aneuploidy and the evidence supporting a role for nonrandom numerical chromosome changes in neoplastic development, as well as significance of aneuploidy in cancer, are discussed.
Sources and more information
Aneuploidy Induction and Cell Transformation by Diethylstilbestrol: A Possible Chromosomal Mechanism in Carcinogenesis, Cancer Research August 1983 43; 3814.
The Journal of Legal Medicine, Volume 4, Issue 2, 1983
An estimated 1000 individual or class action products liability lawsuits have been filed against the pharmaceutical manufacturers of diethylstilbestrol (DES). The field of potential plaintiffs is estimated at 500,000-6,000,000 and there are 150-300 potential defendant manufacturers.
This article addresses the question of whether the current system of tort liability dispenses fair, timely, and uniform justice both to DES claimants and manufacturers and presents a historical perspective on the basis for liability.
Traditional theories of tort recovery are based on negligence, breach of warranty, and strict liability. They place the burden of proof on the claimant to specifically identify the product manufacturer and establish proximate causation. Novel theories of recovery have had to be applied in DES lawsuits, including concert of action and alternative liability. Most of these theories have been unaccepted by trial and appellate courts because of the inability to identify the manufacturer. Even if DES manufacturers were to be held liable under a theory of industry-wide or market share liability, defendants would be called upon to allocate liability among themselves. Many believe that any departure from traditional tort principles should be accomplished by the legislature, not the judiciary. There is not currently a bill before the US Congress dealing specifically with compensation for damages to DES victims. Any model toxic tort legislation should aim to eliminate the benefit inequities as between claimants and the cost inequities in delivering benefits to qualified recipients by the responsible parties. The claimant’s burden of establishing fault should be eliminated in exchange for a claimant’s surrender of a right to sue a third party, and a standardization of compensatory damages. The requirements of specific product identification, duration of exposure, and degree of fault would be eliminated. Jurisdictional requirements and statues of limitation must be drafted to permit recovery for previously unknown injuries. Finally, there should be an overall goal of promptness in recovery. The most equitable solution to problems with the tort system is legislation which deals with the toxic tort problem as a whole and not just on a case-by-case basis.
Theories of recovery for DES damage. Is tort liability the answer?, NCBI, PMID: 6604118, 1983 Jun;4(2):167-200.
Full text: Journal of Legal Medicine, PDF, Volume 4, Issue 2, 1983.
The unthinking development and tragic use of diethylstilbestrol from 1941 to 1971 – without the freshness, clarity, or applicability of DES: The Complete Story (1981), by Cynthia Orenberg, a medical writer and a victim. Robert Meyers begins with the drug’s synthesis in England, and follows its popularization and marketing, there and in the US, as a treatment for threatened miscarriage – to the point that it was prescribed for women with no symptoms or history of miscarriage. (Some of those treated, in fact, were pregnant for the first time.) The beginning of the end came in 1971 with the first published report linking DES to cancer in the female offspring of women who had taken the drug. The frenetic outcome included lawsuits by patients, FDA foot-dragging, and catastrophic medical treatment – elements which Meyers is unable either to disentangle or weave together coherently. In his view, this twisted tale “is preeminently a story of people – the women who took it” and their families; all the other aspects – political, economic, medical – are “really elements that enter the funnel of American health care and come out on the doorsteps of American consumers.” And, rather than give the doctors’ role a hard going-over, Meyers takes a few tired pot-shots. (when a physician-interviewee puts on a white coat: “What was there about wearing that white coat? Did he speak better wearing the coat? With more authority?”) For rigor as well as personal involvement, Orenberg is far superior. Sources: KirkusReviews.com
Archives 16 fevrier 1983 – Page de journal concernant une enquête sur le distilbène. [Gros plan] du médicament. Une jeune patiente dt la mère a pris du distilbène demande conseil a son médecin – Docteur Anne Cabau, Gynécologue – . A2 Midi invite le Professeur Etienne Baulieu, Service de Biologie Hormonale (INSERM). Boîtes de distilbène avec comprîmes roses et d’autres bleus. Images d’archive INA Institut National de l’Audiovisuel.