ASTHMA IN PATIENTS WITH SILICONE BREAST IMPLANTS: REPORT OF A CASE SERIES AND IDENTIFICATION OF HEXACHLOROPLATINATE CONTAMINANT AS A POSSIBLE ETIOLOGIC AGENT Michael R Harbut Brenda C Churchill* IJOH; 1999; 3:73-82 From: Center for Occupational and Environmental Medicine; Wayne State University, School of Medicine, Detroit, Michigan, and *Department of Internal Medicine, Providence Hospital, Southfield, Michigan Address for correspondence: Michael R. Harbut MD, MPH; Wayne State University School of Medicine, Detroit, Michigan, and Center for Occupational and Environmental Medicine, 22255 Greenfield; Southfield, Michigan, 48075 ABSTRACT The following study is of 8 breast implant patients evaluated because of respiratory systems, pruritus and rhinorrhea. The presence of hexachoroplatinate in the implants was noted and support for the hypothesis that this contaminant was related to the symptoms experienced by the patients is presented. Cases of implant related asthma were defined by episodic dyspnea, cough, or breathlessness with onset or worsening after implant placement and objective evidence of reversible airways obstruction, either during the presence or after the removal of the devices. All eight patients were found to have asthma, with airway hyper-reactivity demonstrated by methacholine challenge testing performed in seven patients and by partially reversible obstruction after nebulized administration of a beta-agonist in one patient. Eight patients had urticaria and seven had rhinorrhea. Eight of eight breast implant patients evaluated had findings consistent with asthma. Hexachloroplatinate, a potent sensitizer and component of breast implants, is identified as the likely primary etiologic agent in view of findings consistent with platinosis in these patients, and the demonstration of the leaching of hexachloroplatinate from even intact silicone breast implants. INTRODUCTION Human illness as a result of toxicity of silicone gel breast implants is an evolving and controversial area of medical investigation. The nature of any toxicity has not yet been fully characterized, but at least in part it appears to be consistent with a hypersensitivity process. The medical community is moving away from early reports of an autoimmune process, but has not yet offered a clear explanation for complaints registered by patients who have had the devices placed. There is also significant uncertainty with respect to any responsible agents of toxicity. Silicone breast implants consist of a shell encasing a gel. Both the shell and gel are formulations that include carbon and silicone and traces of many other elements. Saline implants are comprised of a saline fluid contained in a silicone shell casing. From an Occupational Medicine perspective, notable among the agents present in both gel and shell are the metals chromium, nickel, aluminum and platinum. The presence of platinum in the implants occurs as a result of its use as a catalyst in its hexasolvent form (H2PtCl6) in the production of gel and shell. (1). All three metals are known to be associated with occupational athma. Hexachloroplatinate, however, is the most potent of sensitizers reported. There is an extensive medical literature related to the occupational disease entity platinosis and airways reactivity, caused by exposure to complex platinum salts. Respiratory problems in platinum refinery workers were reported as long ago as 1911 and are extensively reviewed in the World Health Organization Monograph of the Internal Program of Chemical Safety. (2). Platinosis or platinum allergy historically refers to the triad of asthma, dermatitis and rhinitis in workers exposed to platinum. Pruritis has also been reported. Platinosis is highly prevalent in workers exposed to platinum with a cumulative prevalent rate 50% or more. The potency of platinum is such that the *TLV-TWA for platinum salts is 2 mcg/cubic meter of air. (6). As a comparison, the TLVs for two other toxic metals, lead and arsenic, are two orders of magnitude greater at 0.15 and 0.2 mg/cubic meter of air respectively. There have been case reports of platinum sensitivity from dental work and jewelry. (3, 4). Platinum asthma can be present before, after, or in the absence of positive skin prick testing. Cold air and methacholine challenge have both been shown to evoke airways hyper-responsiveness in the hexachloroplatinate-exposed lung, in the absence of existing exposure and/or laboratory or abnormal immunologic testing. (5-9). METHODS Eight consecutive patients referred to the clinic with breast implants and various symptoms were included, l993 with extensive histories, including a respiratory history that incorporated the questions from the Epidemiology Standardization Project (10). The patients were questioned about alternative exposure sources, such as occupational metal exposures and platinum-containing dental work. This is done to identify any sources of platinum even in the non-hexasolvent form. Patients were also asked about their surgical history, type of implant (silicone or saline), manufacturer, and whether the implants had ruptured. Symptom onset as related to implant status was also elicited. Pulmonary function testing was done in the eight patients. All had complaints of cough or breathlessness. Methacholine challenge testing was done on 7 patients with fundamentally normal pulmonary function and a beta-agonist (Albuterol) was administered by nebulizer to the patient whose pulmonary function test demonstrated airway obstruction. CASE SUMMARIES: CASE #1: A 31 year old, nonsmoking white female, sales account manager underwent breast augmentation surgery in 1989 using Surgitek silicone implants. There was no evidence of rupture or leakage. She had childhood pneumonia but no respiratory symptoms before implantation. Presenting complaints include exertional dyspnea with wheezing, severe pruritus several times each week, scaling and dry skin, occurring since the implant surgery. The patient had normal resting pulmonary function tests with a positive methacholine challenge test (36% decrease in FEV1). CASE #2: A 47 year old, white female nurse, who is currently a smoker with an 8-pack-year history had breast augmentation surgery in 1970 using Dow Silastic silicone implants. The right breast implant ruptured in 1982, necessitating removal and replacement. In 1992, both implants were removed after rupture of the left implant. Spillage of silicone was confirmed operatively in both 1982 and 1992. The patient presented with complaints of loss of taste sensation, speech difficulty, muscular tics and vesiculations, memory loss, episodic confusion, intermittent rash, pruritus, chronic bronchitis and dyspnea on exertion occurring since 1970. She has coughing spells and has episodes of dyspnea on exertion on exposure to some household chemicals. Symptoms worsened after the 19821992 ruptures. She had a history of nonspecific allergies, bronchitis and pneumonia prior to the implants. The patient had near normal resting pulmonary function tests and a positive methacholine challenge. CASE #3: A 54 years of age, nonsmoking white female teacher underwent breast augmentation in 1975 with silicone gel breast implants. There was no definite evidence of rupture or leakage. The patient presented with severe fatigue, somnolence, chest and upper extremity burning, paresthesias and urticaria. Respiratory symptoms developed over the last two years prior to her evaluation, and included a nonproductive cough, episodic coughing spells, and increasing exertional dyspnea. Prior to the implant surgery, she had a history of bronchitis but no documented allergies. She had near normal resting pulmonary function test and the methacholine challenge test demonstrated a 34% decrease in FEV1. CASE #4: A 58 years of age, white female homemaker who is a smoker with a 33-pack-year history, underwent breast reconstruction and augmentation in 1981 after bilateral prophylactic mastectomies for multiple nonmalignant tumors. The implants were removed and replaced three times as a result of complications, and they were permanently removed in 1993. The patient is convinced that there was leakage, but this is unconfirmed. Presenting complaints included severe, progressive fatigue over the eight years prior to evaluation to the point that she now reports spending up to 75% of her day in bed. She also complained of paresthesias. Respiratory symptoms which began or worsened after the implant surgery include cough, wheezing, multiple episodes of bronchitis, increasingly productive cough and episodic dyspnea. Despite her smoking history, this patient had near normal resting pulmonary function tests. Methacholine challenge test was positive with a 22% decrease in FEV1. CASE #5: A 57 year old white female, employed as a waitress since 1991 underwent breast augmentation with silicone implants in 1974. Suspected leakage was confirmed at surgery in January of 1993 when the implants were replaced with a saline type. She is currently a nonsmoker who quit two years ago. Prior to that, she had accumulated a 9-pack-year history over 38 calendar years. She presented with complaints of constant fatigue, pruritus, and an intermittently productive chronic cough with nocturnal wheezing. She also noted burning paresthesias radiating across the chest and upper extremities. Respiratory symptoms began approximately three years prior to evaluation. She had a history of bronchitis and emphysema prior to the implants, but chronic bronchitis only began three years prior to her evaluation here. The patient had markedly abnormal resting pulmonary function tests with a 29% improvement after administration of 2.5 mg of Albuterol by nebulizer. Therefore this patient probably has asthma superimposed on fixed obstructive lung disease. CASE #6: A 49 years of age, nonsmoking white female homemaker underwent bilateral mastectomies for a diagnosis of extensive fibrocystic disease with small fibroadenomas, locular lobular hyperplasia, and focal intraductal papillomatosis. The mastectomies were followed by reconstruction using Surgical Replicon silicone implants in 1983. Within a few months after the reconstruction, the patient began having leakage around the left implant, which precipitated a rash and cramping pain at the surgical site. Approximately three months later, the implants were removed. Bilateral reconstruction was again performed in 1984 using Heyer Schulte implants. The patient continued to have difficulty with rashes and breast pain until finally the implants were removed in 1989. At surgery, the right implant was found to have ruptured. Presenting complaints included recurrent episodes of erythema and pruritus across the chest and upper extremities, nonproductive cough, rhinorrhea, and wheezing. Prior to the implants the patient had symptoms consistent with hay fever and bronchitis. Methacholine challenge testing showed a 52% decrease in the FEV1 with essentially normal resting pulmonary function. CASE #7: A 48 years of age, white female, mortgage loan officer underwent breast augmentation surgery in 1979 using Surgitek silicone implants. She is currently a nonsmoker who quit smoking 20 years ago after accumulating a 3pack-year history over approximately eight calendar years. She developed hardening of the left implant within a few months, and in 1980 her surgeon "broke this by hand" (closed capsulotomy). Subsequently, she began to have flu-like symptoms, which worsened to include rash and arthralgias. During 1985, she was found to have Hashimoto's thyroiditis and is currently on thyroid replacement. In 1988, the patient became convinced the implants had ruptured, and in 1990, she noticed lumps around the left breast. These were evaluated with various radiographic techniques and found to be nonmalignant. The patient experienced progressive worsening of her symptoms, including intolerable pruritus, joint pains, rashes, and intractable allergy symptoms. As a result, the implants were removed in 1992. The operative report confirmed rupture and leakage. She had respiratory symptoms predating the implants which included chest tightness. She had allergies for which she had received desensitization therapy. Episodic dyspnea has been present since 1981 and became worse after the removal of the implants in 1992. She was seen in the emergency room with inconclusive findings. The patient was found to have a normal resting pulmonary function test and a positive methacholine challenge test with a 20% decrease in FEV1. CASE #8: A 53 year old, nonsmoking white female, secretary underwent a double mastectomy in 1977 followed by reconstructive surgery using Dow Corning silicone implants. In 1993, when the implants were found to have ruptured by radiographic examination, they were removed and replaced by McGhan saline implants. The patient presented with complaints of chronic cough, phlegm, wheezing and dyspnea, the onset of which was approximately seven years after implants. There was progressive worsening and symptoms over the last nine years, including frequent urticaria and rhinorrhea. Past medical history is remarkable for episodic bronchitis and various allergies. The patient was found to have essentially normal resting pulmonary function tests and a positive methacholine challenge test with a 20% decrease in FEV1. DISCUSSION The patients presented with cough, wheezing, a productive cough, rhinorrhea and pruritis. (Table 1). The symptoms began approximately 3 to 192 months after the implantation. Breast implant histories vary widely with respect to manufacturer of original and replacement implants. All but three had implants placed at least once and all but three had implants currently in place at the time of evaluation. Six had implant rupture, either surgically confirmed or suspected. Duration of implant exposure ranged from 4 to 22 years. At the time of evaluation, no reliable methodology existed to analyze urine for the possible presence of platinum. (11). Except for the one patient with severe obstructive lung disease, all had normal chest x-rays and pulmonary function tests (Table 2). All had positive methacholine change testing or improvement after the administration of 2.5 mg albuterol. These eight patients were chosen consecutively from women referred for an occupational medicine assessment who had pulmonary symptoms and a history of breast implantations. The Center for Occupational and Environmental is an Association of Occupational and Environmental Medicine. The referring rheumatologist was aware of platinum contamination and the fact that workers from one manufacturer of the devices (Dow-Corning) had been evaluated at COEM for work-related disease. All 8 patients met the following two criteria for asthma. 1. Symptoms consistent with asthma such as wheezing, episodic cough or episodic dyspnea that began or worsened after the presence of silicone gel breast implants. 2. Reactive airways disease as demonstrated by a positive methacholine challenge test with at least a 20% drop in the FEV1 using 10 mg or less of methacholine; or by significant reversibility of airway obstruction after treatment with the beta-agonist. We hypothesize that hexachloroplatinate is the causative agent for "breast implant asthma." It is likely that it is the etiologic agent for the other symptoms and signs consistent with platinum toxicity reported by this patient population. Although platinum hypersensitivity is considered to be largely IgE mediated, (12), more recent studies have shown other more complex mechanisms of immune system disease. (13, 14, 15). Consistent with more recent data, only one of our patients had elevated IgE levels (Table 3). There is convincing evidence that these patients were exposed to platinum. El-Jamal and Templeton (16) found 4 mg/kg1 of platinum in a breast prosthesis, and Lykissa et al (17) found that in an older, intact, surgically removed silicone gel breast implant, 20-25 mcg/day/250 grams of platinum leaks into a lipid medium at 37 degrees. Asthma was found in these patients during implant presence and after implant removal. This parallels the experience from occupational platinum asthma in which symptoms and bronchial hyper-reactivity can exist long after removal from exposure. (5,18). In this series, however, rupture had occurred in those patients who had undergone implant removal, and consequently, some residual sensitizing agents may have escaped into tissue adjacent to the surgical site. The minimal level of implanted platinum required to produce and maintain symptoms is unknown but in the occupational setting allergies in those exposed to any levels of platinum are considered to be exposure related (19,20) especially considering the high prevalence of allergic lung disease is such workers. Asthma in association with platinum-containing breast implants has not been previously reported. Women with breast implants should be questioned about respiratory symptoms. If there is a positive symptom history consistent with asthma, then the patient should be tested for the presence of reactive airways disease. In women with breast implants perhaps pulmonary function tests should be done on pre-employment examinations, especially if their work will involve exposures to allergenic substances. Prospective studies are warranted to confirm our findings of the association between breast implants and asthma. Furthermore, animal studies could be done to prove that the observed disease was due to the platinum contained in the breast implants. REFERENCES 1. Picha G, Goldstein J. Analysis of the Soft-Tissue Response to Components Used in the Manufacture of Breast Implants: Rat Animal Model. Plastic and Reconstructive Surgery. 1991:87: 490-500. 2. Rosner G, Konig HP, Soenen-Stass D. Environmental Health Criteria Platinum. Geneva: International Programme on Chemical Safety. World Health Organization; 1991 pp 89-93. 3. Sheard C. Contact Dermatitis from Platinum and Related Metals. Archives Dermatol. 1995; 71:357-360. 4. Koch P, Baum HP. Contact stomatitis due to palladium and platinum in dental alloys. Contact Derm., 1996;34:243-247. 5. Mergel R, Dierkes A, Rueckmann A, Bergmann EM, SchultzeWerninghaus G. Absence of relationship between degree of nonspecific and specific bronchial responsiveness in occupational asthma due to platinum salts. Eur. Respir. Journal, 1996; 9, 211-216. 6. 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Breast implants and Urinary Platinum. Clinical Chem. 1994; 40:1787. 12. Murdoch, RD, Pepys J, Huges EG. IgE antibody responses to platinum group metals: A large scale refinery survey. Brit J Indust Med 1986: 43:37-43. 13. Blocksma N, Kubicka-Muranyi M, Schuppe HC, Gleichmann E, Gleichmann H. Predictive immunological test systems: Suitability of popliteal lymph node assay in mice and rats. Crit Rev. Toxicol. 1995; 25:369-396. 14. Norlind, K. Further studies on the ability of different metal salts to influence the DNA synthesis of human lymphoid cells. Int. Arch Allergy Appl. Immun. 1986; 79:83-85. 15. Schuppe HC, Haas-Raida D, Kulig J, Bomer U, Gleichmann E, Kind P. Tcell dependent popliteal lymph node reactions to platinum compounds in mice. Int. Arch allergy Immunol 1992;97: 308-314. 16. El-Jammal, A, Templeton, Douglas M. Measurement of Platinum in Biomedical Silicones by ICP-MS, Analytical Proceedings including Analytical Communications, 1995, 32:293-4. 17. Lykisa E, Kaia S, Hurley J, Lebovitz R. Release of Low Molecular Weight Silicones and Platinum from Silicone Breast Implants, Anal. Chem., 1997; 69:4192-4196. 18. Merget R, Reineke M, Rueckmann A, Bergmann EM, SchultzeWerninghaus G. Nonspecific and Specific Bronchial Responsiveness in Occupational Asthma Caused by Platinum Salts after Allergen Avoidance. Am. J. Respir. Crit. Care Med. 1949;150:1146-1149. 19. Boggs, P. Platinum Allergy. Cutis, 1985; 35:318-20. 20. Harber P, Schenker M, Balmes, J. Occupational and Environmental Respiratory Disease. Mosby-Year Book, Inc, St Louis, Missouri, 1996 pp 500-501. * Editors note: We included this article because it was the occupational medicine background of the author which leads him to make the observed association. Table 1. Patient history and symptoms Patient (No) Age* Atopic history Smoking (pack years) Months to symptoms** Cough Wheezing Puritis Rhinorrhea 1 31 - - 12 - + + + 2 47 + 8 1 +*** - + 3 54 - - 72 + - + + 4 58 - 33 48 + + + + 5 57 - 9-stopped 192 + + + + 6 49 + - 3 + + + + 7 48 + 3 -stopped 12 + + + + 8 53 + - 84 + + + + *age at presentation **months after implantation ***cough was productive in all cases > > >> > > >>Table 2. Pulmonary function tests > > >>Patient FVC* FEV1 FEV1/ FVC FEF25-75 TLC DLCO > > >> Methacholine challenge test** > > >>1 113 118 82 84 93 88 36 > > >>2 129 118 70 60 105 95 36 > > >>3 113 112 75 63 105 105 34 > > >>4 110 104 70 41 101 75 22 > > >>5 66*** 32 37 7 122 65 improved after 2.5 > > >>mg albuterol (by 29%) > > >>6 103 106 78 59 126 91 52 > > >>7 103 114 85 85 118 95 20 > > >>8 124 135 82 92 103 97 28 > > >>*percent of predicted > > >>**percent decrease in FEV1 after the administration of > methacholine > (minimal > > >>dose)