E»-E: }‘L%K ?§%&%¢g:5: {llllllnlk . . ,__. If; A * % N C‘ I, Q; N :8 j ~ GUN vhfaghififfifll 3 ijfiikiéysjw ° « ' f L J \ - K __ ,_ _, .«. 1'. \ «'5' 4 .'-. ~5‘~_ ('1, V.’ at ~*;w««;- 1 ; § -*» A * \.\~Q 4 . _ , .. , ue ‘ago, .; }_é I ‘,\.r'\-V "'”‘-*~. 7 ‘$5.5; E1 ‘x ' " uifx I ‘and’ " bi |\\i\|\\\||\ %i@@@w@a@«i O \\||\\\l|J|ii\i\T|\efl\t\[|)|f\\’1\ LIBRARY OF T CONGRESS . DIETHYLSTILBESTROL (DES) DRUG CONTROVERSY ISSUE BRIEF NUMBER IB75023 AUTHOR: Hartman, Sarah Science Policy Research Division Zegel, Vikki A. Science Policy Research Division THE LIBRARY OF CONGRESS CONGRESSIONAL RESEARCH SERVICE HAJOR ISSUES SYSTEM DATE ORIGINATED 9341942; DATE UPDATED gggggggg FOR ADDITIONAL INFORMATION CALL 287-5700 0115 CRS- 1 ‘ 11375023 UPDATE-01/14/80 I.§§P..13~'...2§El3.1.'£E£QE The diethylstilbestrol (DES) controversy concerns Food and Drug Administration (FDA) and U.S. Department of Agriculture (USDA) regulations for the control of the use of DES as a growth stimulant used in animal feeds or as implants during the final stages of fattening before slaughter. The compound has been linked to the development of cancer in experimental animals, and has been brought under suspicion as causing cancer in female progeny, and possibly causing sterility or testicular cancer in sons, when used by women as an anti-abortifacient. Public attention has focused upon the animal feed issue for a number of years. In June 1979, DES was banned by the FDA for use as a growth promotant in cattle and sheep. Related to this issue, but within a different framework of Federal regulation, is the controversy associated with FDA approval of DB5 for use as a “morning after" birth control pill under selected medical conditions. The Assistant Secretary for Health convened a DHEW-DES Task Force in 1978 to review the public health issues associated with the uses of DES, and to make recommendations to the HEW Secretary. The Task Force issued its final summary report on Sept. 21, 1978. A §AQEQ§Q9.!2..£\.§2..2QL£§.¥.-A!ALI§l§. Diethylstilbestrol (DES) has been associated with the development of cancer in test animals under certain conditions of experimental exposure; Additionally, and this was a critical development, the use of DES as an ' ti—abortifacient (i.e., to prevent spontaneous abortion or.miscarriage) has reen strongly associated with the development of a rare vaginal cancer in the daughters of some women who had been treated during pregnancy.) Studies have also shown a possible association between prenatal" exposure to DES and testicular cancer in men, as well as a link to sterility in the male .offspring of DES-treated mothers. The ’dosages in the test animals and medical usage were admittedly greater than the residues that were being A detected in meat that was being sold on the market place (from slaughtered animals that had been treated with DES as a growth-promoting substance). Nevertheless, the evidence of this potential for cancer initiation by DES resulted in the opinion by FDA that since residues were not being eliminated by existing regulations, then the substance should not be permitted as an animal feed supplement. The regulation permitting the use of DES as an animal feed supplement derives from the so—called “Delaney Clause“ of an amendment to the Federal Food, Drug, and Cosmetics Act (FDCA): 1g1_g;§;g¢_ ggglgljgllz “No suchi regulation shall issue if a fair evaluation of the data before the Secretary- (A) fails to establish that the proposed use of the food additive, under the conditions of use to be specified in the regulation, will be safe: ggggiggg, that no additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, after tests \ .ch are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal, except that this proviso shall not apply with respect to the use of a substance as an ingredient of feed for animals which are raised for food production, if the Secretary finds (i) that, under the CRS- 2 IB7 5023 UPDATE--01/10/8,0 conditions of use and feeding specified in proposed labeling and reasonably certain to be followed in practice, such additive will not adversely affect the animals for which such feed is intended, and (ii) that no residue of the additive will be found (by methods of examination prescribed or approved by the Secretary by regulations, which regulations shall not be subject to subsections (f) and (g) [of the Act]) in any edible portion of such anima after slaughter or in any food yielded by or derived from the living animal; or... ‘II Even though the preceding cited portion of the FDCA has a special provision that allows the use of DES as an animal food supplement, the provisions of this Act prohibit such substances if they are shown to be carcinogenic, and residues remain for ingestion by human beings- Accordingly, the FDA, after long, laborious study, initiated changes in 1973 in the regulations governing the use of DES and prohibited further use of DES either in feeds or as implants in tissue. The U.S. Court of Appeals (Washington, D.C.) ruled on Jan. 24, 1974, that the FDA had acted illegally in 1973 in its ban of the use of DES in cattle feed and for other uses in animals. The court ruled that the FDA must provide a hearing for the makers of the drug, or declare that the use of DES is an immediate health hazard in order to continue its ban. To comply with this court order, FDA in January 1976 again posted a notice of opportunity for hearing on its proposal to withdraw approval of DES for certain uses. A public hearing on this issue began on May 16, 1977. The scheduled hearing phase of the FDA's action was concluded in January 1978. In September 1978, Administrative Law Judge Daniel J. Davidson ruled against the continued use of DES as an animal igrowth promotant. Industry filed exception to the judge's rule. The FDA Commissioner made a decision on June 29, 1979 to revoke the animal drug regulation that approved the uses of DES as an animal feed additive and as a subcutaneous implant to promote growth in cattle ar‘ sheep, thereby effectively banning the substance for such uses. The rulin, was published in the Federal Register, v. an, no. 131, July 6, 1979 (see REFERENCES). ’ A The FDA had encountered technical difficulties in the methods being used for detecting the presence of residues. They established procedures and minimum criteria regulations “to ensure the absence of carcinogenic residues in edible products derived from food-producing animals or color additives." iThe regulations were set forth in the Feb. 22, 1977, Federal Register. Because of the accumulating evidence about the carcinogenicity of DES, the FDA approval of this drug as a post-coital, or "morning- after" birth control wdrug also has been criticized. -It has been charged that despite the recognition that this approval for the drug should limit use to clearly defined "emergencies," such as rape, the drug is being prescribed as a "morning after" pill to prevent pregnancy in far greater quantities than is warranted by the risks associated with the drug. [“Emergency" situations are decided by the patient and her physician.) In addition, new evidence now suggests that DES may in fact increase the mother's risk of developing certain hormone-related cancers, such as that of the breast, cervix, uterine lining, ovaries, and colon. At present, DES is approved for use has a post-coital drug ton prevert pregnancy, although it is not marketed as such. Since it has other bonafi medical uses, DES is manufactured by several drug companies (25-mg. tablets as well as other forms), but it is not marketed or advertised~ for CRS- 3 1375023 UPDATE-01/14/80 contraceptive use. Physicians, of course, may prescribe the drug for this or any other purpose in the course of a patient's medical treatment. In addition to the administrative court action, several suits have been iled in civil courts around the country in which DES daughters have initiated class actions against the manufacturers of the drug. one such suit I has been filed against the University of Chicago and a leading pharmaceutical manufacturer by Assistant Secretary of State Patsy T. Hink and two women who charge that they were unknowingly given DES during pregnancy. In 1978, the Assistant Secretary for Health convened a special DHEw—DES Task Force to review the broad public health issues associated with both the carcinogenic and non-carcinogenic effects of DES. Their first report, making recommendations concerning the issue of breast cancer among DES mothers, was submitted to the Assistant Secretary for Health on May 30, 1978. The final summary report of the Task Force was submitted on Sept. 21, 1978 [see REFERENCES]. Meanwhile, at least one state (New York) enacted legislation in 1978 to provide for a public information campaign on DES to identify and provide care for individuals who have either taken the drug or have been exposed to it prenatally (see CHRONOLOGY). In 1979, "encouraging results“ from a National Cancer Institute-supported study involving several thousand women whose mothers took DES during pregnancy were reported at a meeting of the’ International Academy of Pathology's U.S.-Canadian Division in San Francisco (see REFERENCES). The findings indicate that the risk of developing vaginal cancer among female offspring of DES mothers may be lgggg than was previously thought. Studies *‘ long-term risk are continuing. if I 7 During the 92d and 93d Congresses, a number of bills relating to the DES issue were introduced, but received no final action. ‘These bills ranged from the reinstatement of the use of DES to more stringent regulations to eliminate its use altogether. Legislative action in the 94th Congress was initiated to secure a ban on all uses of DES discussed in this summary but none of the bills were enacted. one DES bill was introduced during the 95th Congress, but received no action. No such legislation has been introduced in the 96th Congress, to date. 1 1 L§§£§LA$£Q§ H.R. 5780 (Hollenbeck) Directs the Secretary of Health, Education, and Welfare to establish a program to alert women who received DES while pregnant of the health hazards of such drug to them and their daughters and to reimburse such women and their daughters for one-half the diagnosis and treatment costs resulting from receiving such drug. Introduced Nov. 1, 1979; referred to Committee on Interstate and Foreign Commerce. §’A§£!§§ U.S.- Congress. House. Committee on Appropriations. Subcommittee on Agriculture, Environmental and Consumer Protection. Agriculture—Environmental, and Consumer Protection Appropriations U056 CBS— 4 IB75023 UPDATE-01/1H/80 for 1975. Food and Drug Administration. Study of the Delaney Clause and other anti-cancer clauses. 'Hearings, 93d Congress, 2d session. may 6, 1974. Washington, U.S. Govt. Print. Off., 1974. 591 p. These hearings include a review of the status of the DES controversy as of the date of the hearings. Included is a comprehensive analysis of the Delaney Clause of the Food, Drug, and Cosmetics Act. The study of the FDCA was completed by a special study group assembled by the FDA and included representatives of the scientific, consumer, and regulatory community. Congress.y House. Committee on Government Operations. A Subcommittee of the Committee. Regulation of diethylstilbestrol (DES) (Its use as a drug for humans and in animal feeds). Washington, U.S. Govt. Print. Off., 1971 and 1972. Hearings held Part 1, Nov. 11, 1971, 111p; Part 2 Dec. 13, 1971, 2u1 p; Part 3 Aug. 15, 1972, 110 p. I 1 Congress. House. Committee on Interstate and Foreign Subcommittee on Health and the Environment. Hearings, 9flth Congress, 1st Dec. 16, 1975. Washington, 78 p. Commerce. Diethylstilbestrol (DES). session, on Title I of S. 963. U.S. Govt. Print. Off., 1976. Committee on Labor and Public Welfare. Regulation of diethylstilbestrol (DES), July 181 p. Congress. Senate. Subcommittee on Health. 1972. Hearings, 92d Congress, 2d session, on S. 2818. 20, 1972. Washington, U.S. Govt. Print. Off., 1973. Congress. Senate. Committee on Labor and Public Welfare. Subcommittee on Health; and Committee on the Judiciary, Subcommittee on Administrative Practice and Procedure.v Regulation of Diethylstilbestrol (DES), 1975. Hearings, 94th Congress, 1st session, on S. 963, Feb. 27, 1975. Washington, U.S. Govt. Print. Off., 1975. 304 p. §§EQ§I§_1.Ul2-§QNGBl3.§§l9.!A.L D0C9.fi§!.'E§ Kennedy, Edward H. A bill to prohibit the use of DES. Statement in the Senate. Congressional record [daily ed.] v. 121, Har. 5, 1975: S3106-S3110. ' Ribicoff, Abraham. DES: a case study of regulatory abdication. Schweiker, Richard S. .A bill to prohibit the use of DES. Remarks in the senate. Congressional record [daily ed.] v. 118, Aug. 2, 1972: 812558-$12560. 1 Statement in the Senate. Congressional record [daily ed.] v. 121, Har. 5. 1975: S3110-S3111. Congress. House. Committee on Government Operations. Regulation of diethylstilbestrol (DES) and other drugs used in food producing animals. Washington, 0.5. Govt. Print. Off., 1973. 87 p. At head of title: 93d Congress, 1st session. House. Report no. 93-708. issue of DES, and other related matters. CRS- 5 IB75023 UPDATE-01/10/80 A detailed study by the Intergovernmental Relations Subcommittee of The Federal Food, Drug, and Cosmetic Act with specific emphasis on the animal drug amendments, the Delaney clause, the safety of new animal drugs, and the Provides a review of the background, controversies, regulations, and actions involved in the issues discussed in the report. UOSO Congress. Drug, and Cosmetic Amendments of 1975. S. 963. At head of title: Committee on Labor and Public Welfare. Food, Report to accompany Washington, U.S. Govt. Print. Off., 1975. 35 p. 94th Congress, 1st session. Senate. Senate. Report no. 9w—264. A report with Committee recommendations for the adoption of S. 963, a bill to prohibit the use of DES in animals intended for use as food, and for other purposes. ----- Regulation of DES. U.S. Govt. At head of title: I10. feeds, and for other purposes. Report to accompany S. 2818.‘ Washington, Off., 1972. 13 p. 92d Congress, 2d session. Print. Senate. Report 92-1088. A report with Committee recommendations for the adoption of S. 2818, a bill to prohibit the use of DES in animal Includes a detailed history of the issues associated with DES. Waxman, Henry A. HEW task force announces findings on DES. Statement in the House. Congressional record [daily ed.) 2§§9y9L9§1g9z.Ev§u2§ 06/29/79 10/00/78 09/21/78 05/30/78 03/30/78 03/03/78 FDA issued a final rule to effectively ban DES for use as an animal growth promotant (see Federal register, July 6, 1979). 6 DHEW Secretary warned women who had received DES during pregnancy, (as well as their exposed daughters and sons) to have regular cancer checkups. Administrative Law Judge Davidson ruled against continued use of DES as an animal growth promotant; (industry filed exception). DHEW-DES Task Force Final Summary report submitted to Assistant Secretary for Health.‘ — PDHEW-DES Task Force recommendations report concerning breast cancer among DES mothers was submitted to the Assistant Secretary for Health. State of New York enacted Chapter 715, Laws of 1978, regarding the identification, screening, diagnosis, care and treatment of persons who have taken DES or who have been exposed to the drug prenatally. First meeting of the DHEW-DES Task Force formed by 01/31/78 01/00/78 05/16/77 02/22/77 02/14/77 01/05/77 11/26/76 03/00/76 02/12/76 01/12/76 08/04/75 CRS- 6 IB75023 UPDATE-01/1n/80 Assistant Secretary for Health to study the entire DES issue. ‘ FDA Advisory Committee on Obstetrics and Gynecology recommended that the FDA should delete from current approval the use of DES to relieve breast engorgement after childbirth . FDA concluded the scheduled hearing phase of its actions regarding DES. FDA began public hearings on its proposal to withdraw approval of the use of DES in animals. The FDA published procedures and minimum criteria regulations regarding carcinogenic residues in animal products intended for human consumption (Federal Register, Part II). The pre—hearing on DES conference continued; date for beginning of public hearings on FDA's proposal regarding DES set for May 16, 1977. The pre-hearing conference on the FDA proposal began. FDA announced a pre-hearing conference (Jan. 5, 1977) to discuss future hearings on the FDA proposal to withdraw approval of new animal drug applications for use of DES in animals used for food for human consumption. FDA determined that hearings requested by manufacturers would be justified. FDA received four requests from manufacturers for hearings on the proposal to withdraw DES from use as a growth promotant in animals. Notice of opportunity was published for hearing on the proposal to withdraw approval of new animal drug applications; [proposal to withdraw approval of the use of DES in animals 6 used for food for human consumption on the ground that the drug results in residues that are unsafe within the meaning of the Delaney anticancer clause of the Federal Food, Drug,, and Cosmetic Act].. (See Federal register. vol. 41, no. 7, % Jan. 12, 1976: 1804-4807.) Deadline for hearing requests was Feb. 11, 1976. Publication of FDA requirement for amendment of the physician “package insert“ for preparations containing DES or closely related drugs. Warning to describe the potential hazard of cancer in postpubertal girls and young women whose mothers had received such drugs during pregnancy. Federal register v. no, no. 150, Aug. 4, 1975-- effective date on or before Oct. 3, 1975. 03/07/75 -—-Effective date of FDA approval of DES as emergency post—coital contraceptive. CRS- 7 IB75023 UPDATE-O1/14/80 O2/27/75 - FDA Federal Register order reinstating the regulations pertaining to diethylstilbestrol for use in cattle and sheep. O2/11/75 —~ USDA Federal Register order changing Federal meat inspection requirement to extend the length of time prior to slaughter (from 7 to 14 days) that cattle and sheep must be withdrawn from feed containing DES. O3/27/74 - FDA Federal Register proposal to revoke test methods for determining DES residues. 01/24/74 -- 0.5. Court of Appeals for the District of Columbia vacated FDA orders withdrawing approval for use of DES in animal feed or as implants. ‘ 10/25/73 -- FDA Federal Register order denied hearings on withdrawal of approval of new animal drugs applications for DES implants. O9/26/73 —-FDA Federal Register proposal for the use of DES as an emergency post-coital contraceptive. O5/03/73 - -FDA Federal Register ordered withdrawing approval of new drug applications for DES in implant form. 12/09/72 -—-FDA Federal Register order revoked regulations pertaining to the use of DES in feeds pursuant to section 512(i) of the FDCA. 11/O0/71 -—-FDA Drug Bulletin published on DES noted contraindications ‘ during pregnancy. ADDITIONAL REFERENCE SOURCES Administrative Law Judge rules against DES. Food chemical news,. Sept. 25, 1978: 76-77. All together on DES? Chemical week, Apr. 6, 1977; 16. Anderson, B., et al. Development of the DES-associated clear-cell carcinoma: the importance of regular screening. Obstetrics and gynecology, March 1979: 293-299. Bibbo, uarluce, n.D., et al. A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy. New England journal of medicine, v- 298, no. 14, Apr. 6, 1978: 763-767. Brozan, Nadine. A new legal tactic in the fight to compensate victims of DES. New York Times, June 27, 1979: C13. Byerley, Walter B. so are they all--all honorable men. A review Fof the DES revocation cases to date. Food, drug and cosmetic law journal, v. 29, no. 9, September 1974: 460-468 Carter, Anne C., u.D., et al. Diethylstilbestrol: recommended CRS- 8 IB75023 UPDATE-O1/14/80 dosages for different categories of breast cancer patients. Report of the Cooperative Breast Cancer Group. Journal of the American Medical Association, may 9, 1977: 2079-2085. Chicago hormone maker fined for exposing workers to DES. New York times, June 18, 1977: C6. Cohn, Victor. Recipients of DES warned to get regular checkups. Washington post, Oct. 5, 1978: A3. - Cole, H.H. et al. On the safety of estrogenic hormone residues in edible animal products. Bioscience, v. 25, no. 1, January 1975: 19-25. . DES-exposed women develop benign stigmata. 0.5. medicine, June 1, 1977: 2, 15. DES hearing phase may be concluded; new data emerges. A Food chemical news. Jan. 16, 1978: 69-70. DES manufacturers named in N.Y. suit. Washington post, Mar. 4, 1976: D20. DES/other estrogens “major cause of breast cancer..." Weekly pharmacy reports ("the green sheet“). Feb. 6, 1978. Disorders of uterus, DES exposure tied. 0.5. medicine, July 15, 1977: 3, 11. Economic consequences of banning the use of diethylstilbestrol in cattle feeding. Washington, U.S. Dept. of Agriculture. Economic Research Service, June 1971. 28 p. “Encouraging results“ reported in Nclésupported DES study. The V. 3‘, DO. 5' 6' 1' 6' 7. Food producing animals. Criteria and procedures for evaluating assays for carcinogenic residues. Rules and regulations established by DHEW, FDA, effective Mar. 23, 1977. Federal register, Part II, Feb. 22, 1977. p. 10412-1ou37. Gass, George H. et al. carcinogenic dose—response curve to oral diethylstilbestrol. Journal of the National Cancer Institute, v. 33, no. 6, December 1964: 971-977. Herbst, Arthur L. et al.i Adenocarcinoma of the vagina. New England journal of medicine, v. 23a, no. 16, Apr. 22, 1971: 878-881. Hoover, Robert et al. Stilbestrol (diethylstilbestrol) and the risk of ovarian cancer. The lancet, Sept. 10, 1977: Hormonally active substances in foods: a safety evaluation. Council for Agricultural Science and Technology (CAST). Report no. 66. February 1977. 109 p. Jukes, Thomas H. Estrogens in beefsteaks. Journal of the American Medical Association, v. 229, no. 1n, Sept. 30, 197a: 1920-1921. CRS- 9 IB75023 UPDATE-01/14/80 Labarthe, Darwin, et al. Design and preliminary observations of National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. Obstetrics and gynecolo9Y: v. 51, no. 4, April 1978: 453—u58. Lyons, Richard D. Chemical tied to cancer is banned as cattle feed. New York Times, June 30, 1979: p. 6. ---- Nader group demands U.S. ban on artificial hormone as cancer risk. New York times, Dec. 13, 1977: C24. HcLachlarn, J.A. et al. Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol. Science. v. 190, no. 4218. Michigan court bars suit linking cancer to a drug used by victims‘ mothers. New York times, May 17, 1977: C22. Hintz, Horton. Anti-miscarriage drug DES adds to mother's ‘ cancer risk. Washington post, Dec. 13, 1977: A1. ---- FDA advisers urge DES curb. Washington post, Feb. 1, 1978: C20. ---- Panel concerned on link of DES to cancer cases. Washington post, June 2, 1978: A8 University, firm sued over DES tests in mothers. Washington post, Apr. 26, 1977: A1, 1u. —---- Women warned on beef liver. Washington post, More on DB5. medical tribune, Mar. 16, 1977: 25. O'Brien, Peter C., et al. Vaginal epithelial changes in young women enrolled in the national cooperative diethylstilbestrol adenosis (DESAD) project. Obstetrics and gynecology, March 1979: 300-308. Odd-shaped uteri mark daughters of DES women. {Medical tribune, July 19, 1978: 3, 22. Offspring of women given DES remain under study. Journal of the American Medical Association, Aug. 29, 1977. 932 p. Risk of cancer, dysplasia for DES daughters found "very low.“ Journal of the American Medical Association, Apr. 13, 1979: 1555. 1 Robboy, Stanley J., et al. Pathologic findings in young women enrolled in the national cooperative diethylstilbestrol adenosis (DESAD) project. Obstetrics and gynecology, March 1979: 309-317. sestili, Mary Ann. Genital tract anomalies and cancer in females exposed in uterg to diethylstilbestrol. Brief report on the CBS-10 IB75023 UPDATE-O1/1Q/80 :dfDESADfprofiect. Public Health Reports, Sept.-Oct. 1977: 743159393 Smith,gfionaldgC. et al. Association of exogenous estrogen and I endometrial carcinoma. New England journal of medicine. v. 293, no. 23, Dec. 4, 1975: 1164-1167. Surgeon General seeks physicians‘ help in DES alert. Science, Jan. 12, 1979: 159. Ten companies sued on disputed drug. New York times, Apr. 21, 1976: C17. Three in suit say drug produced cancer. New York times, iuar. 4, 1976: C14. U.S. Dept. of Health, Education, and Welfare. Food and Drug Administration. Diethylstilbestrol (DES) in edible tissues of cattle and sheep; revocations. Federal register, gv. an, no. 131, July 6, 1979: 39387-39389; 39618-39619. --—-- Public Health Service. National Institutes of Health. DES Task Force summary Report. (Submitted Sept. 21, 1978) [Washington] 1978. 68 p. (DHEW Pub. No. (NIH) 79-1688). ----- Information for physicians. DES exposure ;g_gt§;9. [Washington] 1977: 11 p. (DHEW Pub. No. (NIH) 76-1119) ---- Questionsand answers about DES exposure before birth. [Washington] (DHEW Pub. No. (NIH) 76-1118) 1977: 11 p. ---- were you or your daughter born after 1970? [Washington], 1977. (Pamphlet) Ziel, Harry K., and William D. Finkle. Increased risk of endometrial carcinoma among users of conjugated estrogens. New England journal of medicine. vol. 293, no. 23. Dec. H, 1975: 1167-1170. 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