May 12, 1995
David A. Kessler, M.D.
Food and Drug Administration, Room 1-23
12420 Parklawn Drive
Rockville, MD 20857
The undersigned submits on behalf of the Cancer Prevention Coalition, Inc. (CPC), Samuel S. Epstein, M.D., Chair, and the Center for constitutional Rights, Michael Deutsch, Esq. Legal Director. This citizen petition is based on scientific publications dating back to 1960 which clearly demonstrate the carcinogenicity of silicone gel and polyurethane foam (PUF) breast implants. This evidence is further supported by internal Food and Drug Administration (FDA) memoranda.
The undersigned submits this petition under 21 U.S.C. 321 (n), 361, 362, and 371 (a): and 21 CFR740.1, 740.2 of 21 CFR 10.30 of the Federal Food, Drug, and Cosmetic Act to request the Commissioner of Food and Drugs to issue a medical alert to all women who have had silicone gel breast implants with high priority to those with PUF implants, warning them of their risks of breast cancer and of the need for ongoing medical surveillance.
A. AGENCY ACTION REQUESTED
This petition requests that FDA take the following action:
(1) Immediately issue a medical alert to women who have received silicone gel and PUF breast implants, informing them of the risks of breast cancer.
(2) Pursuant to 21 CFR 10.30 (h) (2), a hearing at which time we can present our scientific evidence.
B. STATEMENT OF GROUNDS
In April 1992, the FDA banned silicone gel breast implants except for use in controlled trials. This decision by the FDA was in response to serious questions raised concerning the health risks of implants. However, despite banning the general use of silicone implants, the agency failed to address the risks of cancer.
Carcinogenicity of Silicone Gel
An unpublished Dow Corning study discovered by the FDA in 1987, demonstrated that subcutaneous injection of silicone gel in rats induced highly malignant and metastatic fibrosarcomas.1 Commenting on these findings, FDA Task Force scientists excluded the possibility that these could be solid state tumors;2 it was further urged that "a medical alert be issued to warn the public of the possibility of malignancy development in humans following long-term implant of silicone breast prostheses." The carcinogenicity of silicone gel was subsequently confirmed following intraperitoneal injection in mice.3
Carcinogenicity of Polyurethane Foam
In a series of publications from 1960 to 1964, Dr. Wilhelm Hueper (Chief of the Environmental Cancer Section at the National Cancer Institute) reported on the induction of carcinomas and/or sarcomas following intraperitoneal or subcutaneous injection of PUF in rats.4,5,6,7 Apart from the induction of carcinomas, the possibility that the sarcomas could have been "solid state tumors" was definitively excluded. Furthermore, Hueper demonstrated the rapid in vivo degradation of PUF.
On the basis of these findings, Hueper warned:
- "Since polyurethane plastics have been used in cosmetic and orthopedic surgery during recent years, these observations are of distinct significance and practical importance,— (and) should caution against the indiscriminate use of polyurethane plastics in medical practice—."4
- "against indiscriminate parenteral use of polyurethane plastics— in medical practice."5
- "It is premature — to conclude from the present absence of carcinogenic (human) responses — that the innocuousness of these materials— is established. — (as) any cancerous reaction— might require an induction period of some 30 years or more."7
On the basis of Hueper's studies, a senior FDA staff scientist concluded in 1991 that "PU[polyurethane] is acting as a straight-forward chemical carcinogen-- and is not an appropriate material for use in breast implants."8
The carcinogenicity of PUF was subsequently confirmed by the induction of fibrosarcomas and carcinomas in rats following intraperitoneal and intrapulmonary administration, respectively.9,10 The authors excluded the possibility that the sarcomas were "solid state tumors, "and emphasized that their findings were "consistent with a mechanism of biological degradation."10
Carcinogenicity of Contaminants and Degradation Products of Polyurethane Foam
2,4 - Diaminotoluene (TDA) and 2,4 - toluene diisocyanate (TDI) have been demonstrated to be carcinogenic contaminants and degradation products of PUF in both in vitro and in vivo studies.11,12,13,14,15,15 Additionally, TDA has been identified in both the urine and breast milk of women with silicone gel breast implants.17,18,19 It was accordingly concluded in 1994 that "TDA release from PU foam covers of -- breast implants will undoubtedly produce delayed adverse health effects."16
The carcinogenicity of TDI in mice and rats was first reported in 1983.20 Of particular interest was the induction of a statistically significant incidence of mammary fibroadenomas, besides malignant tumors in other sites in rats. On the basis of these data the International Agency for Research on Cancer (IARC) determined that there was "sufficient evidence" of TDI's carcinogenicity in mice and rats, including the induction of mammary tumors in female rats.21 These conclusions were subsequently reiterated by the National Toxicological Program.22 TDI is currently regulated by: the Environmental Protection Agency (EPA), under the Clean Air Act (CAA), Comprehensive Environmental, Response, Compensation and Liability Act (CERCLA), Resource Conservation and Recovery Act (RCRA), and Superfund Amendments and Reauthorization Act (SARA); the Occupational Safety and Health Administration (OSHA) under the Hazard Communication Standard and as a Chemical Hazard in laboratories; and by the FDA as an indirect food additive.
There is substantial evidence on the carcinogenicity of TDA dating back to 1955. when it was found that subcutaneous injection induced local sarcomas in rats.23 Invasive and metastatic liver cancer was subse-quently induced in rats fed with TDA.24 It is worthy of note that on the basis of these data, the cosmetic industry voluntarily eliminated the use of TDA in hair dyes in 1971. A statistically significant incidence of benign and malignant mammary tumors was induced in rats fed with TDA;25 these tumors developed after only one month feeding. A statistically significant incidence of liver cancer and vascular tumors was induced in mice, and benign and malignant breast tumors, besides tumors in other sites, were induced in rats following feeding of TDA.26 On the basis of these data, IARC concluded that there was "sufficient evidence " of the carcinogenicity of TDA in mice and rats.27 These conclusions were reiterated by the National Toxicology Program, which further warned that "the presence of TDA, even as a trace contaminant, may be a cause of cancer."28
TDA is currently regulated by EPA as a priority hazardous substance under SARA; OSHA under the Hazard Communication Standard as a Chemical Hazard in laboratories; and by the FDA which requires warning labels on coal tar hair dyes containing TDA under the Federal Food Drug, and Cosmetic Act.
An unpublished Congressionally-mandated NCI report emphasized that concerns on "a carcinogenic hazard were recently heightened by reports that the polyurethane foam coating that envelopes the silica gel -- may dissolve and produce the chemical 2,4 diaminotoluene (TDA) -- linked to increased rates of breast and hepatocellular carcinomas in rats and mice and possibly also sarcomas and lymphomas in mice."29
Carcinogenicity of Ethylene Oxide
Ethylene oxide (ETO) has been routinely used to sterilize breast implants. A July 11, 1988 FDA audit of Cooper Surgical revealed a wide range of deficiencies in control procedures, including the absence of formalized procedures for methods for sterilization and aeration, and for failure to test for residues. These concerns are of particular significance as ETO residues are known to persist on medical products, including plastics, even after seven days aeration.30,31 ETO is a well-recognized carcinogen inducing breast cancer, malignant lymphomas and other cancers in mice, and leukemia, brain tumors and other cancers in rats following inhalation, and fibrosarcomas in mice following subcutaneous injection.32
Epidemiological studies on Women with Silicone Breast Implants
Based on a cohort of 11,676 women in Alberta receiving silicone gel or saline implants from 1973 to 1986, with a mean follow-up of only 10.2 years, a deficit of breast cancer was reported. PU implants were not used in Alberta during the study period.33 In a subsequent study with a median follow-up of only 10.6 years, deficits of breast cancer in implanted women and of all other malignancies combines were reported. However, based on small numbers, an increased incidence of lung, vulva, and invasivce cervical carcinomas, were reported.34
However, as emphasized by an NCI report, these studies are seriously flawed,a dn clearly not exculpatory.35 Furthermore, NCI urged longitudinal studies on women with various types of implants. NCI stated: "This call for further study reflects the paucity of available data on long-term effects of augmentation mammaplasty. Most studies evaluating breast cancer risk have lacked systematic case ascertainment and estimates of expected risk. In the two large-scale epidemiologic studies, only scant information on possible disease covariates was available, limiting the ability to evaluate observed relationships. In addition, the devices evaluated were for the most part markedly different in design and material from those currently in use. Thus, further follow-up of a large cohort of women is needed, with particular attention given to effects of specific types of implants.35 Senior FDA scientists have also confirmed that sufficient time has not elapsed to record epidemilogically significant increases in human malignancies involving silicone gel implants.2
C. CLAIM FOR CATEGORICAL EXCLUSION
A claim for categorical exclusion is asserted pursuant to 21 CFR 25.24 (a) (11).
The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representatives data and information known to the petitioner which are unfavorable to the petition.
This petition is submitted by:
Samuel S. Epstein, M.D.
Michael Deutsch, Esq., Legal Director, Center for Constitutional Rights, New York
- FED. Reg. 55:20568--20577, 5/17/90
- FDA staff scientists Drs. Lorentzen, Luu, sheridan & Stratmeyer. Internal agency memoranda, August and September, 1988.
- Potter, Journal of the National Cancer Institute, 86:1058-1065, 1994.
- Hueper, Journal of the American Medical Association, 173:860, 1960.
- Hueper, American Journal of Clinical Pathology, 34:334-337, 1960.
- Hueper, Pathol. Microbiol. 24:77-106, 1961.
- Hueper, Journal of the National Cacner Institute, 33:1005-1027, 1964.
- Mishra, April 1991, Memo to the Director, FDA Office of Device Evaluation.
- Autian et al, Cancer Res. 35:1591-1596, 1975.
- Autian et al, Cancer Res. 36:3973-3977, 1976.
- Guthrie & McKinney, Anl. Chem. 49:1676-1680, 1977.
- Batich et al. J. Biomed. Mater. Res. 23:311-319, 1989.
- Guidoin et al, Ann. Plastic Surg. 28:342-353, 1992.
- Amin et al (Bristol Myers), J. Biomed. Mater. Res. 27:655-666, 1993.
- Benoit, J. Biomed.. Mater. Res. 27:1341-1348, 1993.
- Luu et al. J. Appl. biomater. 5:1-7, 1994.
- Chan et al, Clin. Chem. 37/12:756-758, 1991.
- Chan et al, Clin. Chem. 37/2:2143-2145, 1991.
- Aegis Analytical Laboratories, Press Release: 2,4-TDA Analysis with Regards to PUF Breast Implants, 6/4/91.
- National Toxicology Program, NTP Crcinogenesis Tech. Report No. 82-2, 1983.
- International Agency for Research on Cancer, 39:287-323, 1986.
- National Toxicology Program, Seventh Annual Report on Carcinogens, Summary, 383-387, 1994.
- Umeda, Gann 46:597-603, 1955.
- Ito et al, Cancer Res. 29:1137-1145, 1969.
- DuPont, Phenylenediamines, Unpublished Report to the Office of Toxic Substances, EPA, 1974.
- Weisburger et al, J. Environ. Pathol. Toxicol. 2:325-326, 1978.
- International Agency for Research on Cancer, 19:303-340, 1979.
- National Toxicology Program, Seventh Annual Report on Carcinogens, Summary, 143-146, 1994.
- Brinton, National Cancer Institute, Protocol for a Follow-Up Study of Women with Augmentation Mammaplasty, Report to Congress, 11/93.
- International Agency for Research on Cancer, 19/36:189-226, 1985.
- Agency of Toxic Substances and Disease Registry, (DHHS), A Toxicological Profile for Ethylene Oxide, 63-64, 1990.
- National Toxicology Program, Seventh Annual Report on Carcinogens, Summary, 205-210, 1994.
- Berkel et al. New England Journal of medicine, 326:1649-1653, 1992.
- Deapen & Brody, Plastic Reconstr. Surg. 89:660-665, 1992.
- Brinton, National Cancer Institute, Protocol for a Follow-up Study of Women with Augmentation Mammaplasty, Report to Congress, 11/93.
FDA Response (February 13, 1997)
Petition denied in view of the fact that "There is no evidence that has clearly linked these materials with cancer in humans."