The retreat from precaution: Regulating diethylstilbestrol (DES), endocrine disruptors, and environmental health

Environmental History

Volumn 13, Issue 1, 2008, Pages 41-65

  Langston, Nancy ^a  

^a UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANCER; ENDOCRINE DISRUPTOR; HEALTH RISK; INFERTILITY; REGULATORY FRAMEWORK; REPRODUCTIVE HEALTH;

NORTH AMERICA; UNITED STATES;

ANIMALIA;

EID: 41549120196     PISSN: 10845453     EISSN: None     Source Type: Journal    
DOI: 10.1093/envhis/13.1.41     Document Type: Article

References (96)

1. Ted Schettler, "Endocrine Disruptors: The State of the Science," Greater Boston Physicians for Social Responsibility (1997); accessed online at http://web.archive.org/web/19990220214027/ www-psr.org/tedfs.htm.
2. For critiques of the precautionary principle, see the essays in Julian Morris, ed., Rethinking Risk and the Precautionary Principle (Oxford, UK: Butterworth-Heinemann, 2000).
3. Sonja Boehmer-Christiansen argues that the precautionary principle evolved out of the German concept of Vorsorgeprinzip, which developed in the socio-legal tradition of the 1930s democratic socialism. Vorsorgeprinzip centered on the concept of good household management, and the concept justified state involvement in planning of the economy, technology, morality, and social initiatives. The precautionary principle became an explicit tenet of environmental policy in West Germany during the 197os, and in 1984 was introduced internationally at the First International Convention on the Protection of the North Sea, and has since become a central principle of consumer and environmental protection policy in the European Union. The 1992 Rio Declaration on Environmental and Development was explicitly grounded in precaution. In 1998, a group of thirty-five scientists, policy makers, and advocates concerned about evidence of endocrine disruption developed the Wingspread Statement, a consensus statement on precaution. Andrew Jordan and Timothy O'Riodan, "The Precautionary Principle in Contemporary Environmental Policy and Politics," in Protecting Public Health and the Environment: Implementing the Precautionary Principle, ed. Carolyn Raffensperger and Joel Tickner (Washington, DC: Island Press, 1999), 15-36.
4. See, also, Sonja Boehmer-Christiansen, "The Precautionary Principle in Germany-Enabling Government," in Interpreting the Precautionary Principle, ed. Tim O'Riordan and James Cameron (London: Earthscan Publications, 1994), 3.
5. Letter, Walter Campbell, Commissioner of FDA, to Merck & Co, re NDA 4076, 11/3/41. In FDA, National Archives and Records Administration at College Park, Maryland, (hereafter NARA). RG 88, Records of the Food and Drug Administration, Ai, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 Nov-Dec.
6. For example, in several cases during 1947, the FDA argued that workers in DES manufacturing facilities who complained of sterilization and cancer had "failed to provide material proof" that DES had caused their illness, so there was no need to restrict DES: "Quantitative data are lacking. The data on carcinogenesis is meager and many published opinions are not property backed up on the facts. I personally doubt if most or not all of the people who have raised the question have failed to provide material proof of their contention. The other side, however, has adequate proof of the lack of carcinogenic activity of the estrogen. To be on the safe side, however, I would suggest to these people that female employees be screened to eliminate any who may have a family history of carcinoma." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1947. Folder 526.1. Handwritten notes by FDA staff on the Letter, Richard Waugh, Technical Director, Arapahoe Chemicals, Inc. to Dr. Robert Stormont, FDA. June 26,1947. Letter was circulated within the FDA for handwritten and initiated comments.
7. For a sociological perspective on the initial DES approval process, see Susan Bell, "The Synthetic Compound Diethylstilbestrol, (DES) 1938-1941: The Social Construction of a Medical Treatment" (PhD diss., Brandeis University, 1981).
8. An examination of DES technology is in Julie Sze, "Boundaries and Border Wars: DES, Technology, and Environmental Justice," American Quarterly 58 (2006): 791-814.
9. Roberta J. Apfel and Susan M. Fisher have examined the development of DES in To Do No Harm: DES and the Dilemmas of Modern Medicine (New Haven: Yale University Press, 1984).
10. Diana Dutton's "DES and Drug Safety" chapter in her book Worse Than the Disease: Pitfalls of Medical Progress (Cambridge: Cambridge University Press, 1988) contains important material for understanding DES.
11. Popular works on DES include Cynthia Laitman Crenberg, DES: The Complete Story(New York: St. Martin's Press, 1981);
12. Stephen Fenichell and Lawrence S. Charfoos, Daughters at Risk: A Personal DES History (New York: Doubleday, 1981),
13. and Robert Meyers, DES: The Bitter Pill (New York: Seaview/Putnam, 1983).
14. For a review of the scientific literature on DES effects, see: R. M. Giusti, K. Iwamoto, and E. E. Hatch, "Diethylstilbestrol Revisited: a Review of the Long-term Health Effects," Annals of Internal Medicine 122 (1995): 778-88.
15. DES in beef is examined in Sze, "Boundaries and Border Wars," and in Alan Marcus, Cancer from Beef: DES, Federal Food Regulation, and Consumer Confidence (Baltimore: Johns Hopkins University Press, 1994).
16. Intersex effects on sons of DES mothers are summarized in Scott P. Kerlin, "The Presence of Gender Dysphoria, Transsexualism, a nd Disorders of Sexual Differentiation in Mates Prenatally Exposed to Diethylstilbestrol: Initial Evidence from a 5-Year Study," paper presented at 6th Annual E-Hormone Conference New Orleans, October 27-30, 2004; accessed online at http://www.desexposed.org/aboutdes/ dessons5yrstudy.html.
17. Nelly Oudshoorn, Beyond the Natural Body: An Archeology of Sex Hormones (London: Routledge, 1994), 26, 39.
18. Joanne Meyerowitz, How Sex Changed: A History of Transsexuality in the United States (Cambridge: Harvard University Press, 2002), and Oudshoorn, Beyond the Natural Body.
19. Bell, "The Synthetic Compound Diethytstilbestrol," 15 ff.
20. As one researcher on DES, Dr. Edward Davis, stated in an interview with the FDA in 1940, the point of DES was to control natural fluctuation in hormones. "The essential treatment for the alleviation of menopausal symptoms ... was to administer 1 milligram of Stilbestrol orally each day for a period of three months; then to decrease the dosage to 1/2 milligram per day for three months, followed by 1/2 milligram every other day for three months, and finally 1/2 milligram two times a week for three to six months. If the drug is discontinued too soon, symptoms will recur. Dr. Davis aims by this method of treatment to gradually decrease the amount of estrogenic substance in the body and believes by this matter to be able to avoid the symptoms which are so common at the menopause." Memorandum of interview. Dr. M. Edward Davis, University of Chicago, and Dr. Ernest Q. King, Medical Officer of the FDA. Nov. 1, 1940. in FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-.11.
21. See the review in E. C. Dodds et al., "Synthetic Oestrogenic Compounds Related to Stilbene and Diphenylethane. Part 1. "Proceedings of the Royal Society of London. Series B, Biological Sciences 127 (1939): 140-67.
22. See, also, E. C. Dodds et al., "Oestrogenic Activity of Certain Synthetic Compounds," Nature 141 (1938): 247-49.
23. Thanks to an anonymous reviewer for suggesting this perspective. Philip Hilts, in Protecting America's Health: The FDA, Business, and One Hundred Years of Regulation (NewYork: Knopf, 2003), 72-107, explores the controversies over the regulatory power of the FDA.
24. Bell notes that "The medical science represented by the production of DES involved negotiations among clinical investigators, officials at the FDA, and pharmaceutical manufacturers over how to judge DES, as well as whether it was safe prior to its release for sale. DES was not the first drug to be reviewed after the passage of the 1938 Act. However, it was the first drug that was not lifesaving and possibly unsafe. In addition, more drug manufacturers submitted applications to market DES than for any other drug up to that time. Thus, it was used by FDA officials as an occasion to clarify procedures and to set policy for future cases." Susan Bell, "Gendered Medical Science: Producing a Drug For Women," Feminist Studies, 21 (1995): 469-500.
25. These studies were included in the annotated bibliography prepared by Merck and Co., April 1941, submitted to the FDA. Stilbestrol (Diethylstilbestrol): Annotated Bibliography (Rahway, NJ: Merck and Co., Inc., April 1941).
26. R. L. Noble, in October 14, 1938, published a study titled "Functional Impairment of the Anterior Pituitary Gland Produced by the Synthetic Oestrogenic Substance 4:4' Dihydroxy-[alpha: beta]-diethylstilbene," Journal of Physiology 94 (1938): 177-83.
27. Bernhard Zondek and Felix Sulman wrote, "While after absorption the hormone esters are rapidly rendered inactive in the organism, this is not the case with stilboestrol. In the excreta large amounts of the active substance are found. The fact that the organism is unable to inactivate considerable amounts of stilboestrol probably helps to explain its eventual toxicity (compared with oestrone)." Cited in Stilbestrol (Diethylstilbestrol): Annotated Bibliography, 10.
28. Deborah Cadbury, Altering Eden: The Feminization of Nature(NewYork: St Martin's Press, 1999), postscript.
29. See E. C. Dodds and W. Lawson, "Synthetic Estrogenic Agents without the Phenanthrene Nucleus," Nature 137 (1936): 996;
30. and E. C. Dodds and W. Lawson, "Molecular Structure in Relation to Oestrogenic Activity: Compounds without a Phenanthrene Nucleus," Proceedings of the Royal Society. London B. 125 (1938): 222-32.
31. FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974-1940. Folder 526.1-.11. Memorandum of interview. Dr. U. J. Salmon (NY) and Dr. Gordon A. Granger, Medical Officer of the FDA. July 13, 1940. A doctor reported that the wife of another doctor in his practice had developed breast cancer after being treated with estrogens derived from horse urine. She was described as having "gone crazy" when she learned she had breast cancer after "receiving estrogens over a long period of time for premenstrual headaches and later on had received them for the menopause. There was no way to determine with any degree of accuracy the amounts she had received because so many people had been involved in the administration. Both he and Dr. Duke had administered various preparations in various strengths both by hypodermic and by mouth." Kohn went on to dismiss the possibility that these supplemental estrogens could have been linked to Mrs. Duke's breast cancer, on the grounds that "Mrs. Duke had a carcinoma background since her mother had died of a malignancy." He added that "in spite of Mrs. Duke's experience, he had no qualms about administered estrogens.... he then said he thought the Administration was going too far in the warning and caution direction." FDA, National Archives and Records Administration at College Park, Maryland. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-.11. Memorandum of interview. Dr. C. Kohn, Kansas City, MO, and Dr. Gordon A. Granger, Medical Officer of the FDA. July 26, 1940.
32. Dr. William Stoner wrote to James Durrett that while all estrogens were problematic, synthetic ones were likely to be even worse, because they were novel substances in evolution: "It was stated that the mammalian organism has become accustomed to the action of certain hormones which may produce damage although they usually do not, while other substances having actions simulating those of the natural hormones, such as synthaline, dinitrophenol, stilbestrol, etc., more or less uniformly cause damage with which the organism has not learned to cope." FDA, FIO. DES Microfiche # 166. Folder 159. Letter, Dr. William H. Stoner, Medical Research Division, Schering Corporation, to James Durrett, FDA. July 6, 1939.
33. For example, in January 1940 the FDA sent out a press release to the Science News Letter stating that stilbestrol was "effective but potentially dangerous," citing the American Medical Association and its Council on Pharmacy as authorities. The press release warned that "Liver damage and cancer are among the possible dangers seen in use of the new synthetic hormone. The medical profession in general is advised not to use it until further studies have been made by experts... because these products have proved cancer-inducing in animals." Press clipping from Science News Letter, January 13, 1940. "Synthetic female hormone pills considered potential danger," in FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974, 1940. Folder 526.1-.13.
34. Letter, W. G. Campbell, Commissioner, to Mr. Charles Dunn, NYC, July 1940 (full date unreadable in microfilm). FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-.32. Another researcher interviewed by the FDA staff, Dr. I. Penchars, "pointed out that he did not know what the dangerous dose of estrogen was nor did he know what a safe dose of estrogen was nor did he know how to find out. He pointed out that with our state of knowledge in this condition, it was inadvisable to permit such a product to be part of a cosmetic used for indiscriminate distribution." Memorandum of interview (follicular hormone in cosmetics. Dr. Hans Lisser, Dr. I. Penchars, Dr. Allen Palmer, Dr. I. Perry (San Francisco), with Dr. R. W. Weilserstein of FDA. Sept. 3, 1940. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-.13.
35. As FDA Commissioner Walter Campbell wrote in a letter to Merck: "In conclusion it might be well to again state that the main reason for the suggested revision of this sentence is conservatism, and in our judgment the public interest may well be served by the exercise of conservatism with respect to this drug at this time." Letter, W. G. Campbell, Commissioner of FDA, to Merck & Co., re NDA 4076,11/3/41. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 Nov-Dec.
36. Richard Gillam and Barton J. Bernstein, "Doing Harm: The DES Tragedy and Modern American Medicine," The Public Historian 9 (Winter 1987): 57-82.
37. For example, in one interview, James Durrett wrote: "Dr. Nelson then took a bottle of 1 mgm Stilboestrol Tablets (Burroughs & Welcome) from his desk and asked for information concerning the preparation. He said Burroughs & Welcome has sent them to him and requested a clinical trial." Memorandum of interview. Dr. Harry M. Nelson, Detroit, and Dr. Gordon A. Granger, Medical Officer of the FDA. 1/19/40. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974.1940. Folder 525.03-526.
38. A woman named Agnes Sullivan wrote to President Franklin Roosevelt demanding that DES be made available; James Durrett wrote back to Sullivan: "Your recent letter addressed to President Roosevelt has been referred to this Administration for consideration and reply." Durrett went on to add that DES was not available because "it has not been sufficiently investigated by experts to show that it is safe for use." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-32. Letter, J. J. Durrett to Mrs. Agnes M. Sullivan, Elizabeth. NJ, Sept. 16, 1940. By the following winter, pressure on the FDA to approve the drug was mounting as media attention increased. An article in Reader's Digest promised that women would find welcome relief from the horrors of menopause if only the FDA would approve DES: "Called by one clinician 'the most valuable addition to our therapy in recent years,' the first synthetic estrogen, diethylstilbestrol... awaits only the approval of the Federal Food and Drug Administration as a 'new drug' before being placed on the market as an inexpensive, orally-administered therapeutic agent for the relief of the menopause and other conditions.... Stilbestrol will be welcomed because it will extend the treatment of one of the most distressing of natural body processes: the emotional stress, irritability, mental depression, exhaustion, and physical upsets that accompany 'change of life' in women between the ages of 40 and 50." Media clipping,
39. Helen Haberman, "Help for Women Over Forty," from Reader's Digest November 1941. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974.1941. Folder 526.1 Nov-Dec.
40. Dr. James Davis from Statesville, North Carolina, wrote to the FDA on Feb. 4, 1941: "Is there a possibility that the manufacturers will be able to put this [drug] on the market any time soon? My experience with this drug has been so satisfactory that I feel it should be available." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974.1941. Folder 526.1 January to July. Letter, Dr. James W. Davis (Statesville, NC) to Dr. J. J. Durrett, FDA. 2/7/41.
41. Susan Bell analyzes the contents of these case reports in "Gendered Medical Science."
42. James C. Whorton, Before Silent Spring: Pesticides and Public Health in Pre-DDT America, (Princeton: Princeton University Press, 1974), 225.
43. FDA, FIO. DES Microfiche #166. Folder 159. Memorandum to Dr. Herbert C. Calvery RE: Literature on Stilbestrol, Feb. 29, 1940.
44. Hugh Auchincloss, a scientist at Columbia, was one of the most prominent researchers leading the charge against DES on suspicion of cancer. Joined by a fellow researcher, Cushman Haagensen of Columbia, and by the editor of The Journal of the American Medical Association, Auchincloss warned in JAMA of "the danger of cancer from the now widely used female sex hormone treatment." Auchincloss identified one case of breast cancer developing in a woman who had been treated with estrogen (not diethylstilbestrol) for just over two years, while the JAMA editor noted that among forty-three women treated with estrogen in England, three of them had development "cancer of the womb." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974-1940. Folder 526.1-.13. Press clipping from The Press-Scimitar, Memphis, Tennessee, May 20, 1940. "Cancer danger in hormone use." The lawsuit against the American Medical Association made other scientists unwilling to risk testifying against pharmaceutical companies. For example, Dr. Robert T. Frank, a scientist whom the FDA had wanted to testify in a case against a topical estrogen cream, refused because of his bitterness over the way "he had been treated when making his deposition in the A.M.A.-Endocreme case. He referred to the personal abuse heaped upon me both before and since testifying." Memorandum of interview. Dr. Robert T. Frank, New York, and Dr. Gordon A. Granger, Medical Officer of the FDA. July 11, 1940. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-11. For a revealing summary of the endocreme case, see Memorandum 10/1/41. George Larrick, Acting Chief, New Drug Division, to Walter Campbell, Commissioner. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974-1941. Folder 526.1. October.
45. For example, one doctor expressed concern that label warnings "might bring repercussions on the physician should a patient develop carcinoma during estrogenic therapy." Memorandum of interview. Dr. Samuel Sorkin, Chicago, and Dr. Gordon A. Granger, Medical Officer of the FDA. August 1, 1940. in FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1940. Folder 526.1-.11.
46. The FDA required all manufacturers in 1941 to include the warning: "The administration of stilbestrol is contraindicated if the patient is in the age group where continued ovarian function and fertility are desirable, due to the alleged inhibitory activity of stilbestrol on anterior pituitary function." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 Nov-Dec. letter, W. G. Campbell, Commissioner of FDA, to Merck & Co., re NDA 4076, 11/3/41. On October 23, 1941, Dr. Joseph Rosin of Merck asked the FDA to justify the inclusion of this statement. Commissioner Walter Campbell replied: "First and primarily, we feel that promotional material regarding stilbestrol should be extremely conservative in order that practitioner may not be encouraged to use the drug in conditions where deleterious results may ensure. In our judgment, a few instances of sterility produced by this drug would be cause for serious concern on the part of all interested parties, and particularly so if the descriptive literature did not forthrightly inform the practitioner that such a consequence is a possibility." FDA, NARA. RG 88, Records of the Food and Drug Administration, Al, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 Nov-Dec. letter, W. G. Campbell, Commissioner of FDA, to Merck & Co, re NDA 4076, 11/3/41. Merckwrote back again, insisting that some doctors felt DES wouldn't impair fertility, and Commissioner Campbell replied: "A goodly number of qualified experts have recommended that the administration of the drug be restricted in the manner suggested by the sentence under discussion. A discussion as to the merits of the different viewpoints held by experts in this field would not appear to be particularly fruitful at this time.... In conclusion it might be well to again state that the main reason for the suggested revision of this sentence is conservatism, and in our judgment the public interest may well be served by the exercise of conservatism with respect to this drug at this time." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 Nov-Dec. letter, W. G. Campbell, Commissioner of FDA, to Merck & Co, re NDA 4076.
47. In a memo to all stations, the FDA office wrote: "We quote for your information and guidance the Administration's June 1, 1942 letter to West District...While the possibility of developing a prosecution based on the over-the-counter sale of a dangerous drug received in interstate commerce is still being considered, only the most carefully chosen case will be discussed with the General Counsel's office initially ... As of course you know, some question has been raised as to the applicability of the terms of the Federal law to over-the-counter sales of products.... When the courts are called upon to give judgment in a matter of this kind, we would like to have the decision based on a case which involves a more serious public health hazard than is exhibited by stilbestrol.... For this purpose one of the sulfanilamide drugs in table form would be particularly appropriate, since the element of danger could be convincingly demonstrated." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974.1942a. Folder 526.1.-.10-526.3-.66 Memo, W. R. M. Wharton, Chief, Eastern District, to Stations, Eastern District. 6/25/42.
48. In October of 1945, Abbott asked the FDA to allow them to drop warnings: "In view of the satisfactory clinical experience with Diethylstilbestrol during recent years, we suggest the Food and Drug Administration permit the omission from our labels of the statement, "Warning-This is a potent drug and serious consequences may result if used other than under constant medical supervision." The FDA wrote back: "As you point out, experience during the last four years has demonstrated that with therapeutic dosages of this drug the toxic reactions have not been greater, either in number or severity, than those seen with therapeutically equivalent amounts of the natural estrogens. For this reason, we are inclined to agree with you that the warning quoted above is no longer necessary on preparations of diethylstilbestrol in the usual dosage forms." FDA, FIO. DES Microfiche # 20, folder 11, Letter, Edgar B. Carter, Associate Director of Research, Abbott Laboratories, to Dr. Walton Van Winkle, Jr. FDA, 10/ 3/ 45. And FDA, FIO. DES Microfiche # 20, Folder 11. Letter, P. B. Dunbar, Commissioner of Food and Drugs, FDA, to Mr. Edgar B. Carter, Abbott Laboratories, 10/26/45.
49. In 1946, Karnaky wrote to Squibb requesting more experimental drug samples, "I would like to have you continue sending me the 25 mg stilbestrol each month for at least 12 more months.... I would like to continue playing with stilbestrol and see what other uses we can work out for it. Personally, I believe it is a wonderful drug." FDA, Freedom of Information office, 5600 Fisher Lane, Rockville, Maryland (hereafter FIO). DES Microfiche # 35, Folder 18/4/19, Letter from Dr. Karnaky to Dr. Newcomer of E.R. Squibb and Sons, 1946. In another instance, he "offered to finance the funeral costs 'up to $1000' of anyone who died from an excessive dose" of DES. Karnaky to King, June 3, 1947, Karnaky File, FDA records; cited in Gillam and Bernstein, "Doing Harm," 67. The Karnaky quote about the drug companies is also from Gillam and Bernstein, "Doing Harm," 67.
50. FDA, FIO. DES Microfiche # 26, Folder 17, NDA 4056. Material from H. Sidney Newcomer, Medical Department, E.R. Squibb and Sons, to R. P. Berwick, FDA. 4/28/47.
51. White's work, limited to diabetic women, lacked controls and did not indicate how many women had even been given various hormones, or in what combinations. P. White, "Pregnancy Complicating Diabetes," The Journal of the American Medical Association 128 (May 19, 1945): 181-82;
52. and White and Hazel Hunt, "Pregnancy Complicating Diabetes," Journal of Clinical Endocrinology 3 (September 1943): 500-11.
53. For criticisms of this work, see David Hurwitz and Katherine Kuder, "Fetal and Neo-natal Mortality in Pregnancy Complicated by Diabetes Mellitus," The Journal of the American Medical Association 124 (January 29, 1944): 273-75;
54. and the comments of William Dieckmann in White, "Pregnancy Complicating Diabetes," 182. The Smiths'1946 study provided data on neither efficacy or safety; they described the outcome from only one woman's pregnancy: Olive W. Smith, George V. S. Smith, and D. Hurwitz. 1946. Increased excretion of pregnanediol in pregnancy from diethylstilbestrol with special reference to the prevention of late pregnancy accidents," American Journal of Obstetrics and Gynecology 51 (1943): 411-415.
55. Described in Gillam and Bernstein, "Doing Harm," 68.
56. See also Olive Smith, "Diethylstilbestrol in the Prevention and Treatment of Complications of Pregnancy," American Journal of Obstetrics and Gynecology 56 (1948): 821-34.
57. FDA, FIO. DES Microfiche # 26, Folder 17, NDA 4056. Material from H. Sidney Newcomer, Medical Department, E.R. Squibb and Sons, to R. P. Berwick, FDA. 4/28/47. This file includes testimonies from doctors who gave DES to their patients and reported on the outcomes to Dr. Newcomer. The doctors' names and the patients' names have been removed from the files. The specific testimony regarding "excessive shopping" is from a letter to Dr. Newcomer dated November 19, 1946.
58. These studies were included in the annotated bibliography prepared by Merck and Co., April 1941, submitted to the FDA. Stilbestrol (Diethylstilbestrol):Annotated Bibliography.
59. Noble, "Functional Impairment of the Anterior Pituitary Gland," 177-83. Just months after the synthesis of DES, Noble's work showed that the injection into rats of DES in oil solutions was followed by atrophy of the testes, prostate, and seminal vesicles in the male, ovarian atrophying in the female, and an increase in the weight of the adrenals and pituitary in both sexes. Low doses of DES were often more toxic than high doses, so DES didn't follow the normal dose-response relationships expected by toxicology. This observation led some scientists within the FDA to urge particular caution, while leading other scientists and regulators within the FDA to dismiss its potential for harm.
60. For example, R. R. Greene et al. (1939) showed that DES modified embryonic sexual development in the male rat: "Eighteen male and 28 female offspring were delivered by 12 or 30 rats which had been treated with diethylstilbestrol from the 12th or 13th day of pregnancy until a day or two before the expected date of delivery. ... In both males and females the external genitalia of the newborn were of the female type and nipples were present," in Stilbestrol (Diethylstilbestrol): Annotated Bibliography, 7.
61. A French researcher, E. Wolff, showed that DES altered sexual development in chicken embryos (1939), while J. H. Gaarenstroorn (1939) showed that when chicken eggs were injected with DES on the second day of brooding, all the hatchlings were female-no cocks were hatched. Albert Raynaud (1939) also showed feminization of male embryos when their mothers were treated with DES, while R. R. Greene et al. (1940) showed that DES injections in pregnant rats (10.0 to 42.0 mgm), the male babies showed inhibition of normal male development-prostates were absent and seminal vesicles were absent. When the male rats were born, their testes appeared normal, but when they reached puberty, their testes developed cryptorchidism. When female rats were born, their genitalia also appeared normal, but when they reached puberty, their vagina and urethra proved to share a common orifice, and the ovaries were excessively small. All in Stilbestrol (Diethylstilbestrol): Annotated Bibliography. A. S. Parkes et al. showed that DES could prevent implantation in rabbits, and that it was "highly effective in interrupting established pregnancy in rabbits." A. S. Parkes, E. C. Dodds, and R. L.Noble, in "Interruption of Early Pregnancy by Means of Orally Active Estrogens," British Medical Journal 2 (1938): 557-59.
62. R. R. Greene, "Embryology of Sexual Structure and Hermaphroditism," Journal of Clinical Endocrinology 4 (July 1944): 335-48.
63. In 1959, a clinician described a case of male intersex in an infant exposed to DES, and cited Greene's essay as having anticipated this effect in humans: N. M. Kaplan, "Male Pseudohermaphroditism: Report of a Case, with Observations on Pathogenesis," NEJM 261 (September 24, 1959): 642-43. Cited in Gillam and Bernstein, "Doing Harm," 70.
64. Rosenblum and Melinkoff, "Preservation of the Threatened Pregnancy," Western Journal of Surgery (1947):601-03. Another researcher noted "the possibility of some latent effects on the reproductive and endocrine system of the infant," Bernard Lapa, "Diethylstilbestrol in the Treatment of Idiopathic Repeated Abortion," New York State Journal of Medicine 48 (December 1, 1948): 2614.
65. Both cited in Gillam and Bernstein, "Doing Harm," 67, 68.
66. Other researchers criticized the research of George and Olive Smith because of its absence of control groups, placebos, and blinding to correct for chance results or bias. David Hurwitz in 1941-who had collaborated with the Smiths-insisted that "studies could not confirm the efficacy of prenatal DES in humans unless patients were assigned, alternately, to a treatment and to a control group, so that results could be compared." David Hurwitz, "Pregnancy Accidents in Diabetes," The Journal of the American Medical Association 116 (February 15, 1941): 645.
67. In 1953, the first double-blind, controlled study of prenatal DES, led by William Dieckmann and published in The American Journal of Obstetrics and Gynecology, indicated that DES "was not effective in preventing miscarriages ... in either seemingly normal or troubled pregnancies. Not only did DES not work, some slivers of evidence actually suggested that it was worse than a placebo." W. J. Dieckmann et al., "Does the Administration of Diethylstilbestrol during Pregnancy Have Therapeutic Value?" The American Journal of Obstetrics and Gynecology 66 (November 1953): 1062-75.
68. D. Lindsey Berkson, Hormone Deception: How Everyday Foods and Products Are Disrupting Your Hormones-and How to Protect Yourself and Your Family (Chicago: Contemporary Books, 2000), 62-63.
69. For a discussion of the regulatory process in livestock, see Marcus, Cancer From Beef, 11-25.
70. For examples, see letter, Mrs. Edgar G. Eder, Chicago, to FDA (answered by Klumpp), December 2, 1940. Response, Klumpp to Eder, January 14, 1941. Response, Eder to Klumpp, January 16, 1941. In FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1941. Folder 526.1 January to July. 49. FDA, NARA.
71. The owner of Arapahoe chemicals of Colorado wrote to the FDA: "Our Company has recently been approached in regard to manufacturing stilboestrol ... as raw materials for pharmaceutical formulation. We know that these materials are all readily absorbed through the skin and by inhalation. It is our belief that the physiological effect of these materials would constitute a decided industrial hazard. In order to properly evaluate the advantages of undertaking the manufacture of synthetic estrogens, it is necessary that we obtain as much information as possible about them in regard to the seriousness of the health hazard involved, recommended precautions for handling, treatment of affected individuals, cumulative effects, etc. We are particularly concerned over the possibility of carcinogenesis through long continued contact with stilboestrol." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974.1947. Folder 526.1. Letter, Richard Waugh, Technical Director, Arapahoe Chemicals, Inc. to Dr. Robert Stormont, FDA. 6/26/47. The FDA responded: "we have your letter of June 26, 1947 requesting information concerning the health hazard involved and the precautions necessary on the manufacture of stilbestrol ... It is our understanding that excessive exposure to the substances may cause marked disturbances of the menstrual function in women and have a devirilizing effect in men. For this reason it might be feasible for you to consider the employment of old rather than young men if adequate precautionary measures cannot be instituted. The question of carcinogenic potentiality of these substances is one which cannot be answered with finality at this time. We regret to be unable to be of much assistance to you in this matter and suggest that you write to the Bureau of Industrial Hygiene of the United States Public Health Service the National Institute of Health, Bethesda, Maryland for further information." FDA, NARA. RG 88, Records of the Food and Drug Administration, A1, Entry 5, General Subject Files, 1938-1974. 1947. Folder 526.1. Handwritten comments by FDA staff on the Letter, Dr. Robert Stormont, FDA, to Richard Waugh, Technical Director, Arapahoe Chemicals, Inc. 7/9/47.
72. Since 1975, the FDA has required drug labeling to include a subsection on a drug's ability to cause birth defects and other effects on reproduction and pregnancy.
73. Editorial staff, "An Environment for Development," Environmental Health Perspectives 107 (1999).
74. For recent research on second and third generation DES effects, see, R. H. Kaufman et al., "Continued Follow-Up of Pregnancy Outcomes in Diethylstilbestrol Exposed Offspring," Obstetrics and Gynecology 96 (2000):483-89;
75. Retha Newbold, "Cellular and Molecular Effects of Developmental Exposure to Diethylstilbestrol: Implications for Other Environmental Estrogens," Environmental Health Perspectives 103, Supplement 7 (1995);
76. Retha R. Newbold et al., "Proliferative Lesions and Reproductive Tract Tumors in Male Descendants of Mice Exposed Developmentally to Dietbylstilbestrol," Carcinogenesis 21 (2000):1355-63.;
77. Retha R. Newbold et al., "Increased Tumors but Uncompromised Fertility in the Female Descendants of Mice Exposed Developmentally to Diethylstilbestrol," Carcinogenesis 19 (1998): 1655-63.
78. Apfel and Fisher, To Do No Harm.
79. Gillam and Bernstein in "Doing Harm" write "In fact, agency regulators, never doubting the drug's efficacy, clearly wanted to approve DES if the explosive safety issue could somehow be defused. By late 1940, perhaps responding to industry suggestions, FDA officials had hatched a plan to do precisely this.... Had the FDA wanted to avoid approving DES, it possessed the statutory authority to do so. Had the agency wished to resist the pressures for approval, it could always have delayed (it had done so before), rejected the Master File tactic ... stressed the unsettling animal data, and given dissident experts a serious hearing," 65-66. While the FDA did accept the Master File, many FDA drug staff and scientists actively resisted the Small Committee's efforts, and never gave up their increasingly bitter fight to block DES approval.
80. Philip Hilts, Protecting America's Health, 119. Hilts describes one agent's remark that inspectors who led the FDA during the 1950s were "the rat-turd counters," 118. The appointment of George Larrick as FDA commissioner in 1954 illustrates how co-opted the FDA was becoming by the industry it was supposed to be regulating. Industry lobbying got Larrick nominated, for Larrick "believed in the mission of the drug industry, and had preached cooperation and harmony between the regulators and the companies as had rose through the ranks," 119.
81. Sze, "Boundaries and Border Wars," 795.
82. Gillam and Bernstein, "Doing Harm," 68.
83. Barbara Seaman, The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth (New York: Hyperion, 2003). "Medical policy on estrogens has been to 'shoot first and apologize later'-to prescribe the drugs for a certain health problem and then see if there is a positive result. Over theyears, hundreds of millions, possibly billions of women, have been lab animals in this unofficial trial. They were not volunteers. They were given no consent forms. And they were put at serious, often devastating risk," 5. A nuanced view of the ways ideas about gender influenced DES research is in Susan Bell, "Gendered Medical Science."
84. FDA, FIO. DES Microfiche # 0004. Folder 3. Dec. 26 1941, Proposed Lilly Circular on stilbestrol, NDA 4041.
85. Ann Dally, "Thalidomide: Was the Tragedy Preventable?" Lancet 351 (1998):1197-99.
86. For a fascinating exploration of contrasts between drug regulation in Germany and the United States, and the ways those contrasts influenced responses to thalidomide, see Arthur Daemmlich, "A Tale of Two Experts: Thalidomide and Political Engagement in the United States and West Germany," Social History of Medicine 15 (2002):137-58.
87. Cadbury, Altering Eden, 48. one possible objection to the argument that few researchers imagined DES could cross the placenta comes from the fact that in 1941, the FDA forbade the use of DES in pregnant women, implying that regulators were concerned about potential effects on the fetus. The DES warning labels, however, show that regulators were not concerned about DES crossing the placenta and causing birth defects; rather, they were concerned that DES could harm the uterus and ovarian function, which would indirectly be a concern for pregnancy.
88. Some doctors and researchers were concerned, just not in the FDA or the industry. In 1949, an editor of The Journal of the American Medical Association warned "one must not lose sight of the fact that there is apossibility that large doses of female sex hormones may affect a male fetus adversely." Reports began coming out in the medical literature about intersex conditions in children exposed to DES in utero. See, for example, A. M Bongiovanni, A. M. DiGeorge, M. M. Grumback, "Masculinization of the Female Infant Associated with Estrogenic Therapy Alone During Gestation: Four Cases," Journal of Clinical Endocrinology 19 (August 1959): 1004-11;
89. N. M. Kaplan et al., "Apparent Masculinization Of Female Fetus Diagnosed as True Hermaphrodism by Chromosomal Studies," Journal Of Pediatrics 60 (1962): 540.
90. Scott Gilbert, "The Genome in its Ecological Context: Philosophical Perspectives on Interspecies Epigenesis," Annals of the New York Academy of Sciences 981 (2002): 202-18.
91. Linda Nash, Inescapable Ecologies: A History of Environment, Disease, and Knowledge (Berkeley and Los Angeles: University of California Press, 2006).
92. USDA, "A Primer on Beef Hormones," February 24, 1999; http://stockholm.usembassy.gov/Agriculture/hormone.html
93. S. Nandi et al., "Estrogen Can Prevent Breast Cancer by Mimicking the Protective Effect of Pregnancy," In Hormonal Carcinogenesis, vol. 4, ed. J. J. Li et al. (London: Springer-Verlag, 2005), 153-65;
94. and L. Rajkumar et al., "Short-Term Exposure to Pregnancy Levels of Estrogen Prevents Mammary Carcinogenesis," Proceedings of the National Academy Science 98 (2001): 11755-59.
95. René Dubos, cited in Joe Thornton, Pandora's Poison: Chlorine, Health, and a New Environmental Strategy (Cambridge: MIT Press, 2000).
96. For a longer discussion, see René Dubos, Mirage of Health: Utopias, Progress, and Biological Change (New York: Harper & Brothers, 1959).