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FILE NAME Talc TALC DATE 1982 DOC TALC024 DOCUMENT DESCRIPTION Medical Journal Article - Ovarian Cancer and Talc law Wate. wth Copyright es Ovarian Cancer and Talc SEARINGS. EE U A Control Study by a protec d cy be emay ee A and ae party re third a by Medicine SM Z 3 Medicine of Los ne Library oo DANIEL W. CRAMER MD WILLIAM R. WELCH MD ROBERT E. SCULLY MD AND CAROL A. WOJCIECHOWSKI RN Opportunities for genital exposure to talc were assessed in 215 white females with epithelial ovarian cancers and in 215 control women from the general population matched by age race and residence Ninety 42.8 cases regularly used talc either as a dusting powder on the perineum or on sanitary napkins compared with 61 28.4 controls Adjusted for parity and menopausal status this difference yielded a relative risk of 1.92 P < 0.003 for ovarian cancer associated with these who had regularly engaged in both practices had an adjusted relative risk of 3.28 P <pr0a.c0t0ic1ecsoWmpoamreend to women with neither exposure This provides some support for an association between talc and ovarian cancer hypothesized because of the similarity of ovarian cancer to mesotheliomas and the chemical relation of talc to asbestos a known cause of mesotheliomas The authors also investigated opportunities for potential talc exposure from rubber products such as condoms or No diaphragms or from pelvic surgery significant differences were noted between cases and controls in these exposures although the intensity of talc exposure from these sources was likely affected by variables not assessed in this study Cancer 372-376 1982 es National T POSSIBILITY that ovarian cancer may be caused | ce by exposure to certain hydrous magnesium sili- the cates such as talc and asbestos has been raised of by sev- eral ae researchers The lack of epidemiologic studies colection regarding this hypothesis prompted talc exposure in a control study us to investigate of ovarian cancer the Heat from From the Departments of Obstetrics Gynecology and Pathol- ogy Boston Hospital for Women Division of the Brigham and Women's Hospital the Department of Epidemiology Harvard School copied chusetts of Public Health and the Department of Pathology Massa- was chusetts General Hospital Harvard Medical School Boston Massachusetts fi Supported by Grant Number ROI CA24209 awarded by the National Institutes of Health DHEW page a Address for reprints Dr. Cramer Department of Obstetrics and this Gynecology Brigham and Women's Hospital Boston MA 02115 on This study could not have occurred without the generous partici- pation of many clinicians and institutions in the greater Boston area material including Dr. Emanuel Friedman of the Beth Israel Hospital Drs Robert Knapp and Thomas Griffiths of the Brigham and Women's Hospital and Sidney Farber Cancer Institute Dr. Arthur Hassett of The the Brockton Hospital Dr. Joel Rankin of the Framingham Union Hospital Dr. Edward Copenhaver of the Lahey Clinic Foundation Dr. James Nelson of the Massachusetts General Hospital Dr. Clement Yahia of the New England Deaconess Hospital Dr. Lalita Gand- bhir of the Pondville Hospital Dr. James Whelton of Saint Elizabeth's Hospital Dr. Stephen Alpert of the Salem Hospital Dr. Richard Hunter of the University of Massachusetts Medical School The su- perb clerical and technical assistance of Ms. Eileen McManus Ms. Sally Cassells and Ms. Christine Peters is also gratefully acknowledged Accepted for publication December 29 1981 Methods The cases studied were women with ovarian cancer diagnosed between November 1978 and September 1981 and identified through the pathology logs or tumor boards of twelve participating hospitals in the Greater Boston area The study was restricted to English ing residents of Massachusetts ranging in age from 18 to 80 years During the study period 297 eligible cases were identified Physicians denied permission to contact their patients in 13 instances Fourteen patients declined to participate and 14 other patients had died or moved before they could be contacted For each of the 256 interviewed cases slides of the surgical specimens were reviewed by two authors W.R.W. or R.E.S Eighteen cases were excluded as nonovarian primaries Each ovarian tumor was classi- fied according to the Histological Classification of Ovarian Tumors of the World Health Organization The present analysis was restricted to 215 white women with epithelial cancers including 39 with tumors of borderline malignancy and their matched controls Control cases were identified through the Massachusetts Town Books annual publications that list residents by name age and address Controls were selected ran- domly from those women who matched cases by precinct of residence race and age within two years Additionally it was required that a subject be excluded 0008-543X 0372 0.75 'American Cancer Society 270 272700 270 as a control i rectomy but prior hystere Women who confident in had been re could not b stance Won 4 were includ lection of th were eventu controls ide 12 of th had moved phones Tw because of : while 20 4 speak Eng 33 refu acterized a matched w one refusa or more rt Intervie number of history m exposures of several 4 exposure | or perinea a confound associate Manteland Boic as the m analysis al.6 was The a SEM f Exp Pelvic sur Pelvic sur to 1950 Use of co Use of di ese * Adju pre- and ik: an cancer September S or tumor he Greater speak- e from 18 gible cases to contact tients dead died or des of the > authors cluded as as classication of nization te women umors of trols assachuresidents cted ran- > by pre- ears Adexcluded No. 2 OVARIAN CA AND TALC Cramer et al 373 as a control if she had had a bilateral salpingo rectomy but subjects were not excluded because of prior hysterectomy or other types of pelvic operations Women who had had pelvic operations were generally confident in their knowledge of whether their ovaries had been removed but the nature of the operations could not be verified by hospital records in each in- stance Women whose statements could not be verified were included or excluded on the basis of their recol- lection of the surgery The 215 controls in this study were eventually obtained a from total of 475 potential controls identified through the Town Books Fifty 12 of the total could not be reached because they had moved died or had disconnected or unlisted phones Twenty % of the total were ineligible oophorectomy because of a history of bilateral while 20 % were of the wrong age or race or did not speak English Of the total potential controls 155 33 refused to participate If the 215 cases are characterized as to ease of matching 121 56 cases were matched with no refusals 58 27 were matched after one refusal and 36 17 were matched only after two or more refusals Interviews were conducted personally to assess a number of factors from the menstrual and reproductive history medical and family history and environmental exposures This report will deal only with the results of several questions related to potential or definite talc exposure by way of contraceptive practices operations or perineal hygiene Subjects were stratified by potential confounders described below and adjusted relative risks associated with these exposures were calculated by the Haenszel procedure as adapted by Rothman and Boice To accommodate other confounders as well as the matched design in the data collection logistic analysis for matched data as described by Breslow et al.6 was also employed Results The average age and standard error of the mean SEM for cases was 53.2 1.0 years and for controls TABLE 1. Characteristics of Cases and Controls Cases Total = 215 Controls Total = 215 Characteristic No. % No. % Educational level completed college Religion Roman Catholic Marital status never married Nulliparous Menopausal status postmenopausal 48 126 46 78 137 22.3 58.6 21.4 36.3 63.7 49 128 24 39 129 22.8 59.5 11.2 18.1 60.0 * Postmenopausal at time of diagnosis for cases or for interview for controls 53.5 1.0 years Table 1 shows other characteristics of subjects Controls were comparable to cases in educational level and religion Cases and controls differed significantly in marital status and parity with parity being the more important discriminator between them Sixty percent of the cases were postmenopausal at the time of diagnosis whereas 60 of controls were postmenopausal Of these 15 cases and 20 controls had had an artificial menopause Parity and menopausal status were considered important potential confounders in this analysis and were adjusted for as described above Relative risks associated with potential talc exposure from contamination on rubber products are explored in Table 2. Although surgical gloves of recent vintage are dusted with starch talc contamination may still be found Thus a history of pelvic operations appendectomy cesarean section hysterectomy and other operations on internal genital organs other than bilateral oophorectomy was determined in cases and controls Excluding operations associated with the di- agnosis or treatment of the ovarian cancer among the cases no excess in the occurrence of pelvic operations was noted The greatest opportunity for talc exposure from surgery occurred before 1950 when talc was the wot The . material SF mR on T this wy pagepage ma was RR copied F from & the es e colection of the 2 National Libraryky ort of : Medicne by Sys a third ogo party agepg and Se may be TABLE 2. Relative Risks RR for Common Epithelial Ovarian Cancers Associated with Potential Talc Exposure from Contamination on Rubber Products Cases Controls Exposure Total No. % with exposure Total Pelvic surgery Pelvic surgery prior to 1950 Use of condomst Use of diaphragmt 215 215 169 169 78 36.3 51 23.7 19 11.2 37 21.9 215 215 191 191 * Adjusted for parity nulliparous parous and menopausal status pre- and postmenopausal No. % with exposure 75 34.9 Crude RR 1.06 Adjusted RR 1.17 95 Confidence limits 0.76-1.79 48 22.3 30 15.7 35 18.3 1.08 0.68 1.24 1.12 0.77 1.19 0.69-1.82 0.41-1.44 0.69-2.05 Restricted to subjects who had ever been married protected by U.S. U.S. Copyright law law SME RS aNaacad t sap 374 law Duration of No. % who Copyright : diaphragm use Total diaphragm use Total used talc on diaphragm Total = U.S. , by ~ less than five years Total diaphragm use five or more years All users aR * 2 Includes all women protec d = status who 13 27 40 used 6 46.2 16 59.3 22 55.0 diaphragm regardless 21 19 85 of marital be ee No. % who used talc on diaphragm Crude RR Adjusted RR 8 38.1 1.39 1.82 11 57.9 19 47.5 1.06 1.35 1.23 1.56 Adjusted for parity and menopausal status 95 Confidence limits 0.42-8.00 0.36-4.17 0.62-3.88 * : mayand : predominantly used dusting dusting powder for surgical gloves to H1o9we5v0er no significant excess excess of pelvic operations prior was observed for cases party cases 1 The patients married chose who at sometime had been third condoms less frequently and diaphragms more a frequently for contraception than the by group but neither difference control cacant nt Condom use is was statistically signifi- Medicine not necessarily associated with talc Medic neMedicine exposure Not all brands of condoms are dusted with talc and lubricants could affect the of from the condom shedding of talc Unfortunately brands of condoms details on specific Library Library exposure is not a were not obtained Similarly talc use use We necessary consequence of diaphragm inquired specifically about the practice of dust- National ing the diaphragm with talc for National ingthe ) Among all subjects who had storage after use Table was diaphragm used a the was was no no significant significant significant significant significant significant significant signifcant excess excess excessexcess excess excess of of cases cases who there of heir regularly stored s ociated who colection ore had used the diaphragm ore ore ore the risk from this the essedessed exposure exposure can be adequately as- greater detail is neededneeded including frequency of from ise and whether the powder was washed off copied prior to se copied Furthermore contraceptive jellies used with the copied iaphragm could affect the in was al tract transport of talc in the gen- was was page page page of TABLE 4. Relative Risks RR for Common Epithelial Ovarian Hygienic practices involving talc were also Specifically we inquired whether studied used talc as women had regularly regularly a dusting powder on the perineum ularly dusted sanitary napkins with or reg- Ninety 42.8 of the talc Table 4 either or both of these cases had talc exposure by of the these routes compared with 61 28.4 controls The The adjusted relative risk < 0.003 with 95 was 1.92 P confidence limits of 1.27-2.89 pared to subjects who had com- 27.9 cases and neither exposure Sixty 48 22.3 controls had either used talc for dusting or on napkins but not both This dif- ference yielded an adjusted relative risk of 1.55 which was of borderline significance P = 0.06 The risk occurred in women who had both greatest on the perineum and exposures use who had on napkins compared to women neither exposure Thirty 14.9 of were in this cases for category compared with 13 6.0 controls an adjusted relative risk of 3.28 P .001 and 95 confidence limits of 1.68-6.42 The teristics of tumors histologic charac- developing in women with perineal exposure to talc did not differ significantly from those in women without perineal In addition the exposure to talc Table 5 proportion of cases with tumors of bor- derline malignancy was identical without perineal among those with and of 123 exposure to talc Twenty 18 cases without the exposure had tumors of bor- Cancers Associated with Talc Exposure in Perineal Hygiene on material material 3 material No perineal exposure Any perineal exposure The Total = 215 Total = 215 de rr 123 57.2 154 71.6 i 92 42.8 61 28.4 1.89 limits Adjusted RR _ confidence 1.92 ~ 1.27-2.89 * Adjusted for parity and menopausal status As dusting powder but not on napkins Types of perineal exposure On napkins but not as dusting powder Both on napkins and as dusting powder 43 20.0 34 15.8 1.58 1.55 0.98-2.47 17 7.9 14 6.5 1.52 32 14.9 13 6.0 3.08 3.28 1.68-6.42 i ; { : No. 2 j i ' derline maligi the talc expos The argum . cludes four el talc and asbe peritoneal me * epithelial ova ability of tal talc is a speci related to sev in nature with may be cont powders form Epidemiolo and pleural a exposure.10 A been reported with the amo deposits work induce ovaria and suggeste asbestos exp sotheliomas a ruff further * ized the pelv * that environn * cavity via the observed that immediately from the fallo ticism the fir and abnorma that can ente Although I has emerged participants i for epidemio exposure In of the epithel of potential t nificant findi cer and hygi the perineum regularly had had used it o fold increase exposure Se in interpretin The observ characteristic cancer and co may confoun Vol 50 No. 2 OVARIAN CA AND TALC Cramer et al 375 phragm ee jerline malignancy compared to 17 18 of 92 with the talc exposure onfidence imits .2-8.00 6-4.17 2-3.88 studied egularly : or regable 4 sure by 28.49 ) 1.92 P 89 com- 2. Sixty er used his dif, which greatest res use women of cases ontrols nd 95 characerineal n those ible 5 of borith and 187 ) of bor- kins and powder 99 Discussion The argument linking talc and ovarian cancer includes four elements the chemical relationship between calc and asbestos asbestos as a cause of pleural and peritoneal mesotheliomas the possible relation between epithelial ovarian cancers and mesotheliomas and the ability of talc to enter the pelvic cavity The mineral talc is a specific hydrous magnesium silicate chemically related to several asbestos group minerals and occurring in nature with them Generic talc is seldom pure and may be contaminated with asbestos particularly in powders formulated prior to 1976.8.9 Epidemiologic studies have clearly linked lung cancer and pleural and peritoneal mesotheliomas with asbestos exposure An excess of similar pulmonary lesions has been reported in tale workers and seems to be correlated with the amount of asbestos contamination in the talc deposits worked Graham and Graham were able to induce ovarian neoplasms in guinea pigs with asbestos and suggested that ovarian cancer could be related to asbestos exposure noting the similarity between mesotheliomas and ovarian cancers Parmley and Woodruff further emphasized this similarity and popularized the pelvic contamination theory which proposed that environmental carcinogens might enter the pelvic cavity via the genital tract Years earlier it had been observed that inert carbon particles placed in the vagina immediately prior to hysterectomy could be recovered from the fallopian tubes Although greeted with skepticism the finding of talc particles embedded in normal and abnormal ovaries suggests that talc is a substance that can enter the pelvic cavity via the vagina. Although no consensus concerning the risks of talc has emerged from letters editorial and articles participants in the discussion have agreed upon the need for epidemiologic studies of ovarian cancer and talc exposure In this control study of ovarian cancer of the epithelial variety we investigated several sources of potential talc exposure Among these the only significant finding was an association between ovarian cancer and hygienic practices involving the use of talc on the perineum It is especially notable that women who regularly had both dusted their perineum with talc and had used it on sanitary napkins had more than a threefold increase in risk compared to women with neither exposure Several potential biases must be considered in interpreting this association The observation by Wynder et al that menstrual characteristics may differ between women with ovarian cancer and controls might suggest that such differences may confound the association between perineal use of TABLE 5. Characteristics of Ovarian Cancer in Women with and without Perineal Exposure to Talc No perineal use of talc Any perineal use of talc Serous Mucinous Endometrioid and clear cell Other and undifferentiated Total No. % 66 53.7 16 13.0 32 26.0 9 7.3 123 100 No. % 45 48.9 14 15.2 24 26.1 9 9.8 92 100 talc and ovarian cancer We found that menstrual char- acteristics of cases and controls were virtually identical in this study three 24.7 cases complained of moderate or severe dysmenorrhea compared to 56 26.0 controls Twenty 11.6 cases complained of irregular periods compared to 32 14.9 controls The average numbers and SEM of days of flow and cycle length were respectively 4.9 0.1 and 28.9 0.3 days for cases and 4.9 0.1 and 29.6 0.3 days for controls Since entry of talc into the pelvic cavity is prevented by hysterectomy or tubal ligation it might also be argued that the inclusion of subjects with pelvic surgery in the analysis may obviate any association between talc and ovarian cancer It should be noted that such surgery generally occurred near the end of reproductive life for both cases and controls probably after most significant talc exposure had already occurred The exclusion of such subjects from the analysis did not substantially alter the observed associations For example the adjusted relative risk for the use of talc both on the perineum and sanitary napkins was 2.79 P < 0.003 in the group without pelvic surgery compared to 3.28 observed for the entire group In terms of other confounders the association per- sisted after adjustment for menopausal status and parity We also applied multivariate logistic regression for paired observations.6 The maximum likelihood estimate of relative risk associated with any perineal use of talc was 1.61 P = 0.03 with 95 confidence limits of 1.042.49 after simultaneous adjustment for religion marital status educational level ponderal index age at menarche exact parity oral contraceptive or menopausal hormone use and smoking Our sample of cases represents more than 50 of ovarian cancer cases diagnosed in Boston residents in the study period Therefore it is difficult to conceive of a plausible bias in the selection of cases that would yield this excess use of talc There is reason for concern that the high refusal rate among the controls may have introduced a selection bias among the controls But Das The The The material on this page was copied from the colection of the National Library of Medicne by a third party and may be protected by U.S. Copyright law 376 CANCER July 15 1982 Vol 50 when we restricted the analysis to the 121 cases who were matched without a control refusal we again found lawa significant association between talc use and ovarian cancer For women who had used talc bothin dusting Copyrioghtf anadnd on the perineum we found an adjusted relative risk 2.44 P < 0.05 Interviewer biasis also unlikely to explain the association Of the 18 women who were U.S. U.S.initially interviewed as ovarian cancer cases but later byexcluded as having metastatic tumors to the ovary only one 5.6 had both perineal and napkin exposure as compared with 15 in cases and % in controls protecctedompared Experimental data which might bear on the carci- A+be nogenicity of talc come primarily from models using may may pleural implantation of various mineralsin rats These and data suggest that carcinogenicity is dependent primarily and a upon the shape of the particles with long thin fibers partysuch as those occurring in crocidolite asbestos being most carcinogenic Talc consists primarily of plates but third may contain fibers although voluntary guidelines to limit a a limit the content of asbestisform fibersin consumer tal- by cums were proposed by the cosmetics industryin 1976.19 cums Medicinedei If talc is involved in the etiology of ovarian cancer it is not clear whether this derives from the asbestos of content of talc or from the uniqueness of the ovary which which might make it susceptible to carcinogenesis from Librbaortyhboth talc and other particulates With ovulation entrapmetnt rapment of the surface epithelium of the ovary into the ovarian stroma occurs If present talc or other partic- NationalNational ulates might be incorporated into these inclusion cysts the Apparently the implantation of foreign bodies into the lu- mens of of epithelial lined organs a favorable provides environment for carcinogenesisAlternatively talc environmentmight serve to stimulate entrapment of the surface ep- itheliium thelium and act in the same way that incessant ovu- colection been the latioln ation has ovarian proposed as an etiologic factor for oovarianvarian cancer.21 Given the histologic and clinical di- from versity of ovarian cancer talc exposure is unlikely to copied versitybebe the only cause Undoubtedly reproductive experiences such as pregnancies and perhaps oral contraa ceptiveceptive use play rolein its etiology The possibility wasthatt hat talc exposure interacts with these variables de- ppagaegeserves further investigation this It hoped that this report will stimulate further study this of talc exposure in relation to ovarian cancer Animal on studies helpful on would be to determine whether and un- material der circumstances ovarian induced material what be induced circumstances ovarian tumors may _ material by various talc preparations Epidemiologic studies The should focus on opportunities for excessive vaginal con- The tamination with talc such as when it is repeatedly used in perineal dusting powders or sprays and in or on tampons sanitary napkins or other products intended for intravaginal use More precise details on the exact nature and frequency of the exposure and the amount and specific brand of powder used are essential Opportunities for talc exposure are widespread and pervasive but that should not discourage epidemiologists from studying this potentially important exposure in relation to ovarian cancer 1. Evidenc REFERENCES 1. Graham J Graham R. Ovarian cancer and asbestos Environ Res 1967 115 128 2. Henderson WJ Joslin CAF Turnbull AC Griffiths K. Talc and carcinoma of the ovary and cervix J Obstet Gynaecol Br Commonw 1971 266 272 3. Longo DL Young RC Cosmetic talc and ovarian cancer Lancet 1979 349 351 4. Serov SF Scully RE Sobin LH International Histological Classification of Tumours No. 9. Histological Typing of Ovarian Tumours Geneva World Health Organization 1973 5. Rothman KJ Boice JD Epidemiologic analysis with a programmable calculator NIH Publication No. 79-1649 1979 6. Breslow NE Day NE Halvorsen KT Prentice RL Sabai C. Estimation of multiple relative risk functions in matched control studies Am J Epidemiol 1978 299 307 7. Henderson WJ Hamilton TC Griffiths K. Talc in normal and malignant ovarian tissue Lancet 1979 499 8. Cralley LJ Key MM Groth DH Lainhart WS Ligo RM Fibrous and mineral content of cosmetic talcum products Am Ind Hyg Assoc J 1968 350-354 9. Rohl AN Langer AM Selikoff IJ Tordini A Klimentidis R. Consumer talcums and powders Mineral and chemical characteriza- tion J Toxicol Environ Health 1976 255-284 10. Selikoff IJ Hammond EC eds Health hazards of asbestos exposure Ann NY Acad Sci 1979 1-179 11. Kleinfeld M Messite J Zaki MH Mortality experiences among talc workers A follow study J Occup Med 1974 345- 349 12. Parmley TH Woodruff JD The ovarian mesothelioma Am J Obstet Gynecol 1974 234-241 13. Egli GE Newton M. The transport of carbon particles in the human female reproductive tract Fertil Steril 1961 151 155 14. Anonymous Cosmetic talc powder Lancet 1977 1348 15. Newhouse ML Cosmetic talc and ovarian cancer Lancet 1979 528 16. Roe FJC Controversy Cosmetic talc and ovarian cancer Lancet 1979 744 17. Wynder EL Dodo H Barber HRK Epidemiology of cancer of the ovary Cancer 1969 352-370 18. Stanton MF Layard M Tegeris A et al Relation of particle dimension to carcinogenicity in amphibole asbestoses and other fibrous minerals J Natl Cancer Institute 1981 965-975 19. C.T.F.A. Specification Talc cosmetic Cosmetic toiletry and fragrance association Inc. Issue 10-17 1976 20. Brand KG Johnson KH Buoen LC Foreign body tumorigen- esis CRC Crit Rev Toxicol 1976 353 394 21. Casagrande JT Pike MC Ross RK Louie EW Roy S Hen- derson BE Incessant ovulation and ovarian cancer Lancet 1979 ii 170-172 22. Newhouse ML Pearson RM Fullerton JM Boesen EAM Shannon HS A case control study of carcinoma of the ovary Br J Prev Soc Med 1977 148-153 23. McGowan L Parent L Lednar W Norris HJ The woman at risk for developing ovarian cancer Gynecol Oncol 1979 325 24. Blejer JP Arlon R. Talc A possible occupational and ronmental carcinogen J Occup Med 1973 92 97 344 envi- RICHARD REID E 4 SE : cioecor of cervical c infections ai * 3 Potentiall herpes sim CMV ar lation that prompted b between ger results of ti sibly analog First presen the Cervix Bi ton South Ca From the D. University Sch of Pathology Address for ment of Obst West Outer E The author this manuscri and Grace Sc fellow libraria Richardson of medical re and to Judy F Accepted fo